1
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Biyani M, Isogai Y, Sharma K, Maeda S, Akashi H, Sugai Y, Nakano M, Kodera N, Biyani M, Nakajima M. High-speed atomic force microscopy and 3D modeling reveal the structural dynamics of ADAR1 complexes. Nat Commun 2025; 16:4757. [PMID: 40419486 DOI: 10.1038/s41467-025-59987-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 05/09/2025] [Indexed: 05/28/2025] Open
Abstract
Targeting abnormal dysregulation of adenosine-to-inosine deamination by ADAR enzymes offers a promising therapeutic strategy in cancer research. However, the development of effective inhibitors is impeded by the incomplete structural information on ADAR1 complexes. In this study, we employ a combination of computational 3D modeling and high-speed atomic force microscopy to elucidate the atomic and molecular dynamics of ADAR1. Two distinct interface regions (IFx and IFy) on the surface of the deaminase domain and oligomerization structural models are identified. Single-molecule-level insights into the structural dynamics of ADAR1 reveal the oligomerization of ADAR1 monomers through the self-assembly of deaminase domains. In the presence of the substrate dsRNA, the N-terminal region, including RNA-binding domains, of ADAR1 dimer exhibits a controlled flexible conformation and promotes a stable dimeric interaction with dsRNA for RNA editing. These findings provide the basis for the development of targeted inhibitors to regulate ADAR1 activity in therapeutic applications.
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Affiliation(s)
- Madhu Biyani
- Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan.
| | - Yasuhiro Isogai
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan
| | - Kirti Sharma
- Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan
| | - Shoei Maeda
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hinako Akashi
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yui Sugai
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masataka Nakano
- Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
| | - Noriyuki Kodera
- Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan
| | - Manish Biyani
- BioSeeds Corporation, Ishikawa Create Labo, Nomi City, Ishikawa, Japan.
- Graduate School of Science and Technology, Kwansei Gakuin University, Sanda, Japan.
| | - Miki Nakajima
- Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
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2
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Pu S, Cheng T, Cheng H. Advances in RNA editing in hematopoiesis and associated malignancies. Blood 2025; 145:2424-2438. [PMID: 39869834 DOI: 10.1182/blood.2024027379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/30/2024] [Accepted: 01/12/2025] [Indexed: 01/29/2025] Open
Abstract
ABSTRACT Adenosine-to-inosine (A-to-I) RNA editing is a prevalent RNA modification essential for cell survival. The process is catalyzed by the adenosine deaminase acting on RNA (ADAR) enzyme family that converts adenosines in double-stranded RNAs (dsRNAs) into inosines, which are read as guanosines during translation. Deep sequencing has helped to reveal that A-to-I editing occurs across various types of RNAs, affecting their functions. RNA editing detection is now so sophisticated that we can achieve a high level of accuracy and sensitivity to identify low-abundance edited events. Consequently, A-to-I editing has been implicated in various biological processes, including immune and stress responses, cancer progression, and stem cell fate determination. In particular, a crucial role for this process has been recently reported in hematopoietic cell development and hematologic malignancy progression. Results from genetic mouse models have demonstrated the impact of ADARs' catalytic activity on hematopoietic cells, complemented by insights from human cell studies. Meanwhile, clinical studies have implicated ADAR enzymes and RNA editing events in hematologic malignancies and highlighted their potential as prognostic indicators. In this review, we outline the regulatory mechanisms of RNA editing in both normal hematopoiesis and hematologic malignancies. We then speculate on how targeting ADAR expression and site-specific RNA substrates might serve as a therapeutic avenue for affected patients.
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Affiliation(s)
- Shuangshuang Pu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
- Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
- Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China
| | - Hui Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
- Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China
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3
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Wang LY, Shi J, Wang MF, Liu YM, Guo HS, Wang JC, Jiang S, Liang JQ, Liao XH, Chen SY. Characterization of RNA editing gene APOBEC3C as a candidate tumor suppressor in prostate cancer. Sci Rep 2025; 15:17725. [PMID: 40399289 PMCID: PMC12095616 DOI: 10.1038/s41598-025-00169-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/25/2025] [Indexed: 05/23/2025] Open
Abstract
The human genome encodes 19 adenosine and cytidine deaminase genes, classified as A-to-I versus C-to-U editors. A-to-I editors have been widely identified as a promising therapeutic target in various cancers. Conversely, the investigation into C-to-U editors is relatively limited. This study evaluated RNA-editing genes in prostate cancer (PCa). Notably, the APOBEC3 genes are clustered in terms of their chromosomal locations, and their transcriptional changes exhibit significant positive correlations in both primary PCa and castration-resistant prostate cancer (CRPC). One member of this family, APOBEC3C, is demonstrated here as an androgen receptor (AR)-repressed gene. Consistently, APOBEC3 loci are epigenetically inhibited in PCa progression, with APOBEC3C level lower in PSA-high patients. APOBEC3C-low PCa cohorts exhibit increased resistance to Abiraterone and Enzalutamide. Clinicopathological profiling further confirmed APOBEC3C downregulation along PCa progression to advanced phases (grade IV/V, stage III-IV, and pathological stage T3-4), underscoring its prognostic value. Additionally, APOBEC3C expression inversely correlates with PCa relapse and mortality, and low APOBEC3C levels are linked to unfavorable survival. Notably, integrated analyses identified APOBEC3C as the sole RNA-editing gene with significance in both differential expression and PCa prognosis, and APOBEC3C had the best diagnostic performance among 19 genes. Our efforts provide a foundation for further RNA editors research in PCa diagnosis and therapy, and grant APOBEC3C as a candidate tumor suppressor.
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Affiliation(s)
- Li-Yang Wang
- Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi'an, 710119, China
| | - Ji Shi
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Mo-Fei Wang
- Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi'an, 710119, China
| | - Yi-Meng Liu
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Hong-Shan Guo
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jin-Cheng Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Shu Jiang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jia-Qian Liang
- Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
| | - Xing-Hua Liao
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China.
| | - Shao-Yong Chen
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China.
- Hematology-Oncology Division, Department of Medicine, BIDMC, Harvard Medical School, CLS-432, 330 Brookline Avenue, Boston, MA, 02215, USA.
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4
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Almeric E, Karagozoglu D, Cicek M, Dioken DN, Tac HA, Cicek E, Kirim BA, Gurcuoglu I, Sezerman OU, Ozlu N, Erson-Bensan AE. 3'UTR RNA editing driven by ADAR1 modulates MDM2 expression in breast cancer cells. Funct Integr Genomics 2025; 25:103. [PMID: 40381037 DOI: 10.1007/s10142-025-01611-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/29/2025] [Accepted: 05/02/2025] [Indexed: 05/19/2025]
Abstract
Epitranscriptomic changes in the transcripts of cancer related genes could modulate protein levels. RNA editing, particularly A-to-I(G) editing catalyzed by ADAR1, has been implicated in cancer progression. RNA editing events in the 3' untranslated region (3'UTR) can regulate mRNA stability, localization, and translation, underscoring the importance of exploring their impact in cancer. Here, we performed an in silico analysis to detect breast cancer enriched RNA editing sites using the TCGA breast cancer RNA-seq dataset. Notably, the majority of differential editing events mapped to 3' untranslated regions (3'UTRs). We confirmed A-to-I(G) editing in the 3'UTRs of MDM2 (Mouse Double Minute 2 homolog), GINS1 (GINS Complex Subunit 1), and F11R (Junctional Adhesion Molecule A) in breast cancer cells. RNA immunoprecipitation with ADAR1 antibody confirmed the interaction between ADAR1 and MDM2, GINS1, and F11R 3'UTRs. ADAR1 knockdown revealed decreased editing levels, establishing ADAR1 as the editing enzyme. A reporter assay for MDM2, an oncogene overexpressed mostly in luminal breast cancers, demonstrated that RNA editing enhances protein expression, in agreement with reduced MDM2 protein levels in ADAR1 knockdown cells. Further exploration into the mechanisms of 3'UTR editing events revealed an interaction between ADAR1 and CSTF2, a core component of the polyadenylation machinery, as identified through biotin-based proximity labeling mass spectroscopy, and co-immunoprecipitation experiments. Furthermore, CSTF2 knockdown reduced both ADAR1 and MDM2 protein levels. Our findings highlight implications for MDM2 regulation by ADAR1-dependent 3'UTR RNA editing and present an interplay between RNA editing on 3'UTRs and the mRNA polyadenylation machinery. These results improve our understanding of ADAR1's role in cancer-associated 3' UTR RNA editing and its potential as a therapeutic target.
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Affiliation(s)
- Elanur Almeric
- Department of Biological Sciences, Middle East Technical University (METU), Dumlupinar Blvd. No.1 Universiteler Mah, Cankaya, Ankara, 06800, Türkiye
| | - Deniz Karagozoglu
- Department of Biological Sciences, Middle East Technical University (METU), Dumlupinar Blvd. No.1 Universiteler Mah, Cankaya, Ankara, 06800, Türkiye
| | - Mustafa Cicek
- Department of Biological Sciences, Middle East Technical University (METU), Dumlupinar Blvd. No.1 Universiteler Mah, Cankaya, Ankara, 06800, Türkiye
- Department of Biology, Kamil Ozdag Faculty of Science, Karamanoglu Mehmetbey University, Karaman, Türkiye
| | - Didem Naz Dioken
- Department of Biological Sciences, Middle East Technical University (METU), Dumlupinar Blvd. No.1 Universiteler Mah, Cankaya, Ankara, 06800, Türkiye
| | - Huseyin Avni Tac
- School of Medicine, Department of Basic Sciences, Biostatistics and Medical Informatics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
| | - Esra Cicek
- Department of Biological Sciences, Middle East Technical University (METU), Dumlupinar Blvd. No.1 Universiteler Mah, Cankaya, Ankara, 06800, Türkiye
| | - Busra Aytul Kirim
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Sariyer, Istanbul, 34450, Türkiye
| | - Irmak Gurcuoglu
- Department of Biological Sciences, Middle East Technical University (METU), Dumlupinar Blvd. No.1 Universiteler Mah, Cankaya, Ankara, 06800, Türkiye
| | - Osman Ugur Sezerman
- School of Medicine, Department of Basic Sciences, Biostatistics and Medical Informatics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
| | - Nurhan Ozlu
- Department of Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Sariyer, Istanbul, 34450, Türkiye
| | - Ayse Elif Erson-Bensan
- Department of Biological Sciences, Middle East Technical University (METU), Dumlupinar Blvd. No.1 Universiteler Mah, Cankaya, Ankara, 06800, Türkiye.
- Cancer Systems Biology Laboratory, CanSyL, METU, Ankara, Türkiye.
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5
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Stolc V, Preto O, Karhanek M, Freund F, Griko Y, Loftus DJ, Ohayon MM. RNA-DNA Differences: Mechanisms, Oxidative Stress, Transcriptional Fidelity, and Health Implications. Antioxidants (Basel) 2025; 14:544. [PMID: 40427426 DOI: 10.3390/antiox14050544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 03/29/2025] [Accepted: 04/05/2025] [Indexed: 05/29/2025] Open
Abstract
RNA-DNA differences (RDDs) challenge the traditional view of RNA as a faithful copy of DNA, arising through RNA editing, transcriptional errors, and oxidative damage. Reactive oxygen species (ROS) play a central role, inducing lesions like 8-oxo-guanine that compromise transcription and translation, leading to dysfunctional proteins. This review explores the biochemical basis of RDDs, their exacerbation under oxidative stress, and their dual roles in cellular adaptation and disease. RDDs contribute to genomic instability and are implicated in cancers, neurodegenerative disorders, and autoimmune diseases, while also driving phenotypic diversity. Drawing on terrestrial and spaceflight studies, we highlight the intersection of oxidative stress, RDD formation, and cellular dysfunction, proposing innovative mitigation approaches. Advancements in RDD detection and quantification, along with ROS management therapies, offer new avenues to restore cellular homeostasis and promote resilience. By positioning RDDs as a hallmark of genomic entropy, this review underscores the limits of biological adaptation. Furthermore, the prevalence of guanine-rich codons in antioxidant genes increases their susceptibility to ROS-induced oxidative lesions, linking redox stress, genomic instability, and constrained adaptation. These insights have profound implications for understanding aging, disease progression, and adaptive mechanisms in both terrestrial and space environments.
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Affiliation(s)
- Viktor Stolc
- NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Ondrej Preto
- Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | - Miloslav Karhanek
- Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | | | - Yuri Griko
- NASA Ames Research Center, Moffett Field, CA 94035, USA
| | | | - Maurice M Ohayon
- School of Medicine, Stanford University, Stanford, CA 94305, USA
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6
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Modestov A, Buzdin A, Suntsova M. Unveiling RNA Editing by ADAR and APOBEC Protein Gene Families. FRONT BIOSCI-LANDMRK 2025; 30:26298. [PMID: 40302320 DOI: 10.31083/fbl26298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 05/02/2025]
Abstract
RNA editing is a crucial post-transcriptional modification that alters the transcriptome and proteome and affects many cellular processes, including splicing, microRNA specificity, stability of RNA molecules, and protein structure. Enzymes from the adenosine deaminase acting on RNA (ADAR) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) protein families mediate RNA editing and can alter a variety of non-coding and coding RNAs, including all regions of mRNA molecules, leading to tumor development and progression. This review provides novel insights into the potential use of RNA editing parameters, such as editing levels, expression of ADAR and APOBEC genes, and specifically edited genes, as biomarkers for cancer progression, distinguishing it from previous studies that focused on isolated aspects of RNA editing mechanisms. The methodological section offers clues to accelerate high-throughput analysis of RNA or DNA sequencing data for the identification of RNA editing events.
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Affiliation(s)
- Alexander Modestov
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow, Russia
| | - Anton Buzdin
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
- PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium
| | - Maria Suntsova
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
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7
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Li JB, Walkley CR. Leveraging genetics to understand ADAR1-mediated RNA editing in health and disease. Nat Rev Genet 2025:10.1038/s41576-025-00830-5. [PMID: 40229561 DOI: 10.1038/s41576-025-00830-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2025] [Indexed: 04/16/2025]
Abstract
Endogenous, long double-stranded RNA (dsRNA) can resemble viral dsRNA and be recognized by cytosolic dsRNA sensors, triggering autoimmunity. Genetic studies of rare, inherited human diseases and experiments using mouse models have established the importance of adenosine-to-inosine RNA editing by the enzyme adenosine deaminase acting on RNA 1 (ADAR1) as a critical safeguard against autoinflammatory responses to cellular dsRNA. More recently, human genetic studies have revealed that dsRNA editing and sensing mechanisms are involved in common inflammatory diseases, emphasizing the broader role of dsRNA in modulating immune responses and disease pathogenesis. These findings have highlighted the therapeutic potential of targeting dsRNA editing and sensing, as exemplified by the emergence of ADAR1 inhibition in cancer therapy.
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Affiliation(s)
- Jin Billy Li
- Department of Genetics, Stanford University, Stanford, CA, USA.
| | - Carl R Walkley
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
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8
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Herbert A, Cherednichenko O, Lybrand TP, Egli M, Poptsova M. Zα and Zβ Localize ADAR1 to Flipons That Modulate Innate Immunity, Alternative Splicing, and Nonsynonymous RNA Editing. Int J Mol Sci 2025; 26:2422. [PMID: 40141064 PMCID: PMC11942513 DOI: 10.3390/ijms26062422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
The double-stranded RNA editing enzyme ADAR1 connects two forms of genetic programming, one based on codons and the other on flipons. ADAR1 recodes codons in pre-mRNA by deaminating adenosine to form inosine, which is translated as guanosine. ADAR1 also plays essential roles in the immune defense against viruses and cancers by recognizing left-handed Z-DNA and Z-RNA (collectively called ZNA). Here, we review various aspects of ADAR1 biology, starting with codons and progressing to flipons. ADAR1 has two major isoforms, with the p110 protein lacking the p150 Zα domain that binds ZNAs with high affinity. The p150 isoform is induced by interferon and targets ALU inverted repeats, a class of endogenous retroelement that promotes their transcription and retrotransposition by incorporating Z-flipons that encode ZNAs and G-flipons that form G-quadruplexes (GQ). Both p150 and p110 include the Zβ domain that is related to Zα but does not bind ZNAs. Here we report strong evidence that Zβ binds the GQ that are formed co-transcriptionally by ALU repeats and within R-loops. By binding GQ, ADAR1 suppresses ALU-mediated alternative splicing, generates most of the reported nonsynonymous edits and promotes R-loop resolution. The recognition of the various alternative nucleic acid conformations by ADAR1 connects genetic programming by flipons with the encoding of information by codons. The findings suggest that incorporating G-flipons into editmers might improve the therapeutic editing efficacy of ADAR1.
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Affiliation(s)
- Alan Herbert
- Discovery, InsideOutBio, Charlestown, MA 02129, USA
| | - Oleksandr Cherednichenko
- International Laboratory of Bioinformatics, HSE University, 101000 Moscow, Russia; (O.C.); (M.P.)
| | - Terry P. Lybrand
- Department of Chemistry, School of Medicine, Vanderbilt University, Nashville, TN 37232-0146, USA;
- Center for Structural Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232-0146, USA
| | - Martin Egli
- Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN 37232-0146, USA;
| | - Maria Poptsova
- International Laboratory of Bioinformatics, HSE University, 101000 Moscow, Russia; (O.C.); (M.P.)
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9
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Chen P, Zhou H, Yang X, Zheng Y, Chen Y, Wang P, He H, Liu S, Wang F. A-to-I-Edited miR-1304-3p Inhibits Glycolysis and Tumor Growth of Esophageal Squamous Cell Carcinoma by Inactivating Wnt5a/ROR2 Signaling. Mol Carcinog 2025; 64:552-564. [PMID: 39763297 PMCID: PMC11814914 DOI: 10.1002/mc.23867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/19/2024] [Accepted: 12/02/2024] [Indexed: 02/13/2025]
Abstract
A-to-I RNA editing is a pervasive mechanism in the human genome that affects the regulation of gene expression and is closely associated with the pathogenesis of numerous diseases. This study elucidates the regulatory mechanism of A-to-I edited miR-1304-3p in esophageal squamous cell carcinoma (ESCC). Western blot, immunohistochemistry, and RT-qPCR assays were employed to quantify protein and mRNA expression. Colony formation, Edu, wound healing, and Transwell assays were applied to determine miRNA function. Glycolysis was assessed using glucose uptake and lactate production assay. A dual-luciferase reporter assay confirmed the downstream targets of miRNA, and a xenograft assay demonstrated the efficacy of the miRNA. The A-to-I RNA editing level of miR-1304-3p was observed to increase in KYSE180 and KYSE140 ESCC cells following ADAR1 treatment. Following A-to-I editing, the function of miR-1304-3p in ESCC progression underwent a reversal, shifting from carcinogenic to inhibitory. Wild-type (WT) miR-1304-3p targets IRS1, whereas the edited version targets ROR2. The WT miR-1304-3p, but not the edited version, suppressed the expression and tumor-suppressive effect of IRS1 in ESCC. Conversely, ROR2, a specific downstream target of the edited miR-1304-3p, acted as a tumor promoter in ESCC. Furthermore, A-to-I editing of miR-1304-3p can inhibit glycolysis and inactivate the Wnt5a/ROR2 signaling pathway in ESCC. A-to-I RNA editing alters the function of miR-1304-3p in ESCC by changing its target gene. The edited miR-1304-3p hinders the development of ESCC by inhibiting glycolysis and inactivating the Wnt5a/ROR2 signaling pathway.
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Affiliation(s)
- Peng Chen
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical UniversityFujian Cancer HospitalFuzhouChina
- Fujian Key Laboratory of Translational Cancer MedicineFuzhouChina
- Fujian Provincial Key Laboratory of Tumor BiotherapyFuzhouChina
| | - Hang Zhou
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical UniversityFujian Cancer HospitalFuzhouChina
| | - Xian Yang
- Department of NephrologyFujian Provincial Hospital South BranchFuzhouChina
| | - Yuzhen Zheng
- Department of Thoracic SurgerySixth Affiliated Hospital of Sun Yat‐sen UniversityGuangdongGuangzhouP. R. China
| | - Yujie Chen
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical UniversityFujian Cancer HospitalFuzhouChina
| | - Peiyuan Wang
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical UniversityFujian Cancer HospitalFuzhouChina
| | - Hao He
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical UniversityFujian Cancer HospitalFuzhouChina
| | - Shuoyan Liu
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical UniversityFujian Cancer HospitalFuzhouChina
| | - Feng Wang
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical UniversityFujian Cancer HospitalFuzhouChina
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10
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Yang Y, Sakurai M. Advances in Detection Methods for A-to-I RNA Editing. WILEY INTERDISCIPLINARY REVIEWS. RNA 2025; 16:e70014. [PMID: 40223708 PMCID: PMC11995373 DOI: 10.1002/wrna.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/15/2025]
Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a key post-transcriptional modification that influences gene expression and various cellular processes. Advances in sequencing technologies have greatly contributed to the identification of A-to-I editing sites, providing insights into their distribution across coding and non-coding regions. These developments have facilitated the discovery of functionally relevant editing events and have advanced the understanding of their biological roles. This review presents the evolution of methodologies for RNA editing detection and examines recent advances, including chemically-assisted, enzyme-assisted, and quantitative approaches. By evaluating these techniques, we aim to help researchers select the most effective tools for investigating RNA editing and its broader implications in health and disease.
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Affiliation(s)
- Yuxi Yang
- Research Institute for Biomedical SciencesTokyo University of ScienceChibaJapan
| | - Masayuki Sakurai
- Research Institute for Biomedical SciencesTokyo University of ScienceChibaJapan
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11
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Zhu T, Chu Y, Niu G, Pan R, Chen M, Cheng Y, Zhang Y, Li Z, Jiang S, Hao L, Zou D, Xu T, Zhang Z. Editome Disease Knowledgebase v2.0: an updated resource of editome-disease associations through literature curation and integrative analysis. BIOINFORMATICS ADVANCES 2025; 5:vbaf012. [PMID: 39968378 PMCID: PMC11835235 DOI: 10.1093/bioadv/vbaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/09/2025] [Accepted: 01/23/2025] [Indexed: 02/20/2025]
Abstract
Motivation Editome Disease Knowledgebase (EDK) is a curated resource of knowledge between RNA editome and human diseases. Since its first release in 2018, a number of studies have discovered previously uncharacterized editome-disease associations and generated an abundance of RNA editing datasets. Thus, it is desirable to make significant updates for EDK by incorporating more editome-disease associations as well as their related editing profiles. Results Here, we present EDK v2.0, an updated version of editome-disease associations based on both literature curation and integrative analysis. EDK v2.0 incorporates a curated collection of 1097 editome-disease associations involving 115 diseases from 321 publications. Meanwhile, based on a standardized pipeline, EDK v2.0 provides RNA editing profiles from 48 datasets covering 2536 samples across 55 diseases. Through differential analysis on RNA editing, it further identifies a total of 7190 differential edited genes and 86 242 differential editing sites (DESs), leading to 266 339 DES-disease associations. Moreover, a curated list of 28 160 cis-RNA editing QTL associations, 458 187 DES-RNA binding protein associations, and 21 DES-RNA secondary structure associations are annotated and added to EDK v2.0. Additionally, it is equipped with a series of user-friendly tools to facilitate RNA editing online analysis. Availability and implementation https://ngdc.cncb.ac.cn/edk/.
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Affiliation(s)
- Tongtong Zhu
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuan Chu
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guangyi Niu
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Rong Pan
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ming Chen
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuanyuan Cheng
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuansheng Zhang
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhao Li
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuai Jiang
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Lili Hao
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Dong Zou
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Tianyi Xu
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhang Zhang
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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12
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Kung CP, Terzich ND, Ilagen MXG, Prinsen MJ, Kaushal M, Kladney RD, Weber JH, Mabry AR, Torres LS, Bramel ER, Freeman EC, Sabloak T, Cottrell KA, Ryu S, Weber WM, Maggi L, Shriver LP, Patti GJ, Weber JD. ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.16.633410. [PMID: 39896528 PMCID: PMC11785053 DOI: 10.1101/2025.01.16.633410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from internal and external pressure, including metabolic stress. We tested the hypothesis that the iron- dependent cell death pathway, ferroptosis, is a ADAR1-protected metabolic vulnerability in TNBC by showing that ADAR1 knockdown sensitizes TNBC cells to GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analyses led to the discovery of the proto-oncogene MDM2 contributing to the lipid remodeling in TNBC upon ADAR1 loss. A phenotypic drug screen using a ferroptosis-focused library was performed to identify FDA- approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss to suppress TNBC tumorigenesis. By demonstrating that ADAR1 regulates the metabolic fitness of TNBC through desensitizing ferroptosis, we aim to leverage this metabolic vulnerability to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC.
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13
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Nikkel DJ, Kaur R, Wetmore SD. How Can One Metal Power Nucleic Acid Phosphodiester Bond Cleavage by a Nuclease? Multiscale Computational Studies Highlight a Diverse Mechanistic Landscape. J Phys Chem B 2025; 129:3-18. [PMID: 39720842 DOI: 10.1021/acs.jpcb.4c05875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2024]
Abstract
Despite the remarkable resistance of the nucleic acid phosphodiester backbone to degradation affording genetic stability, the P-O bond must be broken during DNA repair and RNA metabolism, among many other critical cellular processes. Nucleases are powerful enzymes that can enhance the uncatalyzed rate of phosphodiester bond cleavage by up to ∼1017-fold. Despite the most well accepted hydrolysis mechanism involving two metals (MA2+ to activate a water nucleophile and MB2+ to stabilize the leaving group), experimental evidence suggests that some nucleases can use a single metal to facilitate the chemical step, a controversial concept in the literature. The present perspective uses the case studies of four nucleases (I-PpoI, APE1, and bacterial and human EndoV) to highlight how computational approaches ranging from quantum mechanical (QM) cluster models to molecular dynamics (MD) simulations and combined quantum mechanics-molecular mechanics (QM/MM) calculations can reveal the atomic level details necessary to understand how a nuclease can use a single metal to facilitate this difficult chemistry. The representative nucleases showcase how different amino acid residues (e.g., histidine, aspartate) can fulfill the role of the first metal (MA2+) in the two-metal-mediated mechanisms. Nevertheless, differences in active site architectures afford diversity in the single-metal-mediated mechanism in terms of the metal-substrate coordination, the role of the metal, and the identities of the general acid and base. The greater understanding of the catalytic mechanisms of nucleases obtained from the body of work reviewed can be used to further explore the progression of diseases associated with nuclease (mis)activity and the development of novel nuclease applications such as disease diagnostics, gene engineering, and therapeutics.
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Affiliation(s)
- Dylan J Nikkel
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge, Alberta, Canada T1K 3M4
| | - Rajwinder Kaur
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge, Alberta, Canada T1K 3M4
| | - Stacey D Wetmore
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge, Alberta, Canada T1K 3M4
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14
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Chen C, Zhang Z, Liu Y, Hong W, Karahan H, Wang J, Li W, Diao L, Yu M, Saykin AJ, Nho K, Kim J, Han L. Comprehensive characterization of the transcriptional landscape in Alzheimer's disease (AD) brains. SCIENCE ADVANCES 2025; 11:eadn1927. [PMID: 39752483 PMCID: PMC11698078 DOI: 10.1126/sciadv.adn1927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 11/26/2024] [Indexed: 01/06/2025]
Abstract
Alzheimer's disease (AD) is the leading dementia among the elderly with complex origins. Despite extensive investigation into the AD-associated protein-coding genes, the involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized the landscape of ncRNAs and PTM events in 1460 samples across six brain regions sourced from the Mount Sinai/JJ Peters VA Medical Center Brain Bank Study and Mayo cohorts, encompassing 33,321 long ncRNAs, 92,897 enhancer RNAs, 53,763 alternative polyadenylation events, and 900,221 A-to-I RNA editing events. We additionally identified 25,351 aberrantly expressed ncRNAs and altered PTM events associated with AD traits and further identified the corresponding protein-coding genes to construct regulatory networks. Furthermore, we developed a user-friendly data portal, ADatlas, facilitating users in exploring our results. Our study aims to establish a comprehensive data platform for ncRNAs and PTMs in AD to advance related research.
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Affiliation(s)
- Chengxuan Chen
- Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Brown Center for Immunotherapy, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
| | - Zhao Zhang
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA
| | - Yuan Liu
- Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Brown Center for Immunotherapy, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
| | - Wei Hong
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA
| | - Hande Karahan
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jun Wang
- Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center and UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Wenbo Li
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center and UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Lixia Diao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Meichen Yu
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana University Network Science Institute, Bloomington, IN, USA
| | - Andrew J. Saykin
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana University Network Science Institute, Bloomington, IN, USA
| | - Kwangsik Nho
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jungsu Kim
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Leng Han
- Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Brown Center for Immunotherapy, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
- Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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15
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Lamb E, Pant D, Yang B, Hundley HA. A probe-based capture enrichment method for detection of A-to-I editing in low abundance transcripts. Methods Enzymol 2025; 710:55-75. [PMID: 39870451 DOI: 10.1016/bs.mie.2024.11.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
Exactly two decades ago, the ability to use high-throughput RNA sequencing technology to identify sites of editing by ADARs was employed for the first time. Since that time, RNA sequencing has become a standard tool for researchers studying RNA biology and led to the discovery of RNA editing sites present in a multitude of organisms, across tissue types, and in disease. However, transcriptome-wide sequencing is not without limitations. Most notably, RNA sequencing depth of a given transcript is correlated with expression, and sequencing depth impacts the ability to robustly detect RNA editing events. This chapter focuses on a method for enrichment of low-abundance transcripts that can facilitate more efficient sequencing and detection of RNA editing events. An important note is that while we describe aspects of the protocol important for capturing intron-containing transcripts, this probe-based enrichment method could be easily modified to assess editing within any low-abundance transcript. We also provide some perspectives on the current limitations as well as important future directions for expanding this technology to gain more insights into how RNA editing can impact transcript diversity.
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Affiliation(s)
- Emma Lamb
- Genome, Cell and Developmental Biology Graduate Program, Indiana University, Bloomington, Indiana, United States
| | - Dyuti Pant
- Department of Biology, Indiana University, Bloomington, Indiana, United States
| | - Boyoon Yang
- Biochemistry Graduate Program, Indiana University, Bloomington, Indiana, United States
| | - Heather A Hundley
- Department of Biology, Indiana University, Bloomington, Indiana, United States.
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16
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Adamczak D, Fornalik M, Małkiewicz A, Pestka J, Pławski A, Jagodziński PP, Słowikowski BK. ADAR1 expression in different cancer cell lines and its change under heat shock. J Appl Genet 2024:10.1007/s13353-024-00926-4. [PMID: 39641903 DOI: 10.1007/s13353-024-00926-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 12/07/2024]
Abstract
Adenosine deaminase acting on RNA 1 (ADAR1) plays an essential role in the development of malignancies by modifying the expression of different oncogenes. ADAR1 presents three distinct activities: adenosine-to-inosine RNA editing, modulating IFN pathways, and response to cellular stress factors. Following stressors such as heat shock, ADAR1p110 isoform relocates from the nucleus to the cytoplasm, where it suppresses RNA degradation which leads to the arrest of apoptosis and cell survival. In this study, we assessed the expression of ADAR1 across different cancer cell lines. We revealed that the presence of ADAR1 varies between cells of different origins and that a high transcript level does not reflect protein abundance. Additionally, we subjected cells to a heat shock in order to evaluate how cellular stress factors affect the expression of ADAR1. Our results indicate that ADAR1 transcript and protein levels are relatively stable and do not change under heat shock in examined cell lines. This research lays a groundwork for future directions on ADAR1-related studies suggesting in which types of cancer ADAR1 may be a promising target for novel therapeutic approaches.
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Affiliation(s)
- Dominika Adamczak
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Michał Fornalik
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Anna Małkiewicz
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Julia Pestka
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Andrzej Pławski
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32 Street, 60-479, Poznań, Poland
| | - Paweł Piotr Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Bartosz Kazimierz Słowikowski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland.
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17
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Quillin AL, Arnould B, Knutson SD, Flores TF, Heemstra JM. EndoVIA for quantifying A-to-I editing and mapping the subcellular localization of edited transcripts. Methods Enzymol 2024; 710:99-130. [PMID: 39870453 PMCID: PMC11908505 DOI: 10.1016/bs.mie.2024.11.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
Adenosine-to-inosine (A-to-I) editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a prevalent post-transcriptional modification that is vital for numerous biological functions. Given that this modification impacts global gene expression, RNA localization, and innate cellular immunity, dysregulation of A-to-I editing has unsurprisingly been linked to a variety of cancers and other diseases. However, our current understanding of the underpinning mechanisms that connect dysregulated A-to-I editing and disease processes remains limited. Widely used methods require RNA extraction and pooling that ultimately erases subcellular localization and cell-to-cell variation, which may be critical to understanding misregulation. To overcome these challenges, we recently developed Endonuclease V Immunostaining Assay (EndoVIA) to selectively detect and visualize A-to-I edited RNA in situ. In this chapter, we describe in detail how to prepare cell samples, stain A-to-I edited transcripts with EndoVIA, quantify global inosine abundance, and visualize the subcellular localization of inosine-containing RNAs at the single molecule level.
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Affiliation(s)
| | - Benoît Arnould
- Department of Chemistry, Washington University in St. Louis, MO, United States
| | - Steve D Knutson
- Department of Chemistry, Princeton University, Princeton, NJ, United States; Merck Center for Catalysis, Princeton University, Princeton, NJ, United States
| | - Tatiana F Flores
- Department of Chemistry, Washington University in St. Louis, MO, United States
| | - Jennifer M Heemstra
- Department of Chemistry, Washington University in St. Louis, MO, United States.
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18
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He D, Niu C, Bai R, Chen N, Cui J. ADAR1 Promotes Invasion and Migration and Inhibits Ferroptosis via the FAK/AKT Pathway in Colorectal Cancer. Mol Carcinog 2024; 63:2401-2413. [PMID: 39239920 DOI: 10.1002/mc.23818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 09/07/2024]
Abstract
The role of adenosine deaminase acting on RNA1 (ADAR1) in colorectal cancer (CRC) is poorly understood. This study investigated the roles and underlying molecular mechanisms of ADAR1 and its isoforms, explored the correlations between ADAR1 expression and the immune microenvironment and anticancer drug sensitivity, and examined the potential synergy of using ADAR1 expression and clinical parameters to determine the prognosis of CRC patients. CRC samples showed significant upregulation of ADAR1, and high ADAR1 expression was correlated with poor prognosis. Silencing ADAR1 inhibited the proliferation, invasion, and migration of CRC cells and induced ferroptosis by suppressing FAK/AKT activation, and the results of rescue assays were consistent with these mechanisms. Both ADAR1-p110 and ADAR1-p150 were demonstrated to regulate the FAK/AKT pathway, with ADAR1-p110 playing a particularly substantial role. In evaluating the prognosis of CRC patients, combining ADAR1 expression with clinical parameters produced a substantial synergistic effect. The in vivo tumorigenesis of CRC was significantly inhibited by silencing ADAR1. Furthermore, ADAR1 expression was positively correlated with tumor mutational burden (TMB) and microsatellite status (p < 0.05), indicating that ADAR1 plays a complex role in CRC immunotherapy. In conclusion, ADAR1 plays oncogenic roles in CRC both in vitro and in vivo, potentially by inhibiting ferroptosis via downregulation of the FAK/AKT pathway. Thus, ADAR1 serves as a potential prognostic biomarker and a promising target for CRC therapy.
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Affiliation(s)
- Dongsheng He
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Chao Niu
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Rilan Bai
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Naifei Chen
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jiuwei Cui
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
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19
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Jiang B, Chen Z, Zhou J. A novel prognostic risk score model based on RNA editing level in lower-grade glioma. Comput Biol Chem 2024; 113:108229. [PMID: 39383624 DOI: 10.1016/j.compbiolchem.2024.108229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 09/19/2024] [Accepted: 09/27/2024] [Indexed: 10/11/2024]
Abstract
BACKGROUND Lower-grade glioma (LGG) refers to WHO grade 2 and 3 gliomas. Surgery combined with radiotherapy and chemotherapy can significantly improve the prognosis of LGG patients, but tumor progression is still unavoidable. As a form of posttranscriptional regulation, RNA editing (RE) has been reported to be involved in tumorigenesis and progression and has been intensively studied recently. METHODS Survival data and RE data were subjected to univariate and multivariate Cox regression analysis and lasso regression analysis to establish an RE risk score model. A nomogram combining the risk score and clinicopathological features was built to predict the 1-, 3-, and 5-year survival probability of patients. The relationship among ADAR1, SOD2 and SOAT1 was verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) RESULTS: A risk model associated with RE was constructed and patients were divided into different risk groups based on risk scores. The model demonstrated strong prognostic capability, with the area under the ROC curve (AUC) values of 0.882, 0.938, and 0.947 for 1-, 3-, and 5-year survival predictions, respectively. Through receiver operating characteristic curve (ROC) curves and calibration curves, it was verified that the constructed nomogram had better performance than age, grade, and risk score in predicting patient survival probability. Apart from this functional analysis, the results of correlation analyses between risk differentially expressed genes (RDEGs) and RE help us to understand the underlying mechanism of RE in LGG. ADAR may regulate the expression of SOD2 and SOAT1 through gene editing. CONCLUSION In conclusion, this study establishes a novel and accurate 17-RE model and a nomogram for predicting the survival probability of LGG patients. ADAR may affect the prognosis of glioma patients by influencing gene expression.
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Affiliation(s)
- Bincan Jiang
- Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan Province 421001, China.
| | - Ziyang Chen
- Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan Province 421001, China
| | - Jiajie Zhou
- Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan Province 421001, China
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20
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Zhou X, Liu H, Hou F, Zheng ZQ, Cao X, Wang Q, Jiang W. REMR: Identification of RNA Editing-mediated MiRNA Regulation in Cancers. Comput Struct Biotechnol J 2024; 23:3418-3429. [PMID: 39386942 PMCID: PMC11462282 DOI: 10.1016/j.csbj.2024.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 10/12/2024] Open
Abstract
Dysregulation of adenosine-to-inosine (A-to-I) RNA editing has been implicated in cancer progression. However, a comprehensive understanding of how A-to-I RNA editing is incorporated into miRNA regulation to modulate gene expression in cancer remains unclear, given the lack of effective identification methods. To this end, we introduced an information theory-based algorithm named REMR to systematically identify 12,006 A-to-I RNA editing-mediated miRNA regulatory triplets (RNA editing sites, miRNAs, and genes) across ten major cancer types based on multi-omics profiling data from The Cancer Genome Atlas (TCGA). Through analyses of functional enrichment, transcriptional regulatory networks, and protein-protein interaction (PPI) networks, we showed that RNA editing-mediated miRNA regulation potentially affects critical cancer-related functions, such as apoptosis, cell cycle, drug resistance, and immunity. Furthermore, triplets can serve as biomarkers for classifying cancer subtypes with distinct prognoses or drug responses, highlighting the clinical relevance of such regulation. In addition, an online resource (http://www.jianglab.cn/REMR/) was constructed to support the convenient retrieval of our findings. In summary, our study systematically dissected the RNA editing-mediated miRNA regulations, thereby providing a valuable resource for understanding the mechanism of RNA editing as an epitranscriptomic regulator in cancer.
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Affiliation(s)
- Xu Zhou
- Department of Biomedical Engineering, College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Haizhou Liu
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Fei Hou
- Department of Biomedical Engineering, College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Zong-Qing Zheng
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Neurosurgery, Binhai Branch of National Regional Medical Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350209, China
| | - Xinyu Cao
- Department of Biomedical Engineering, College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Quan Wang
- Department of Biomedical Engineering, College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
| | - Wei Jiang
- Department of Biomedical Engineering, College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
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Eisenberg E. Bioinformatic approaches for accurate assessment of A-to-I editing in complete transcriptomes. Methods Enzymol 2024; 710:241-265. [PMID: 39870448 DOI: 10.1016/bs.mie.2024.11.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
A-to-I RNA editing is an RNA modification that alters the RNA sequence relative to the its genomic blueprint. It is catalyzed by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes, and contributes to the complexity and diversification of the proteome. Advancement in the study of A-to-I RNA editing has been facilitated by computational approaches for accurate mapping and quantification of A-to-I RNA editing based on sequencing data. In this chapter we review some of the main computational approaches currently used, describe potential hurdles, challenges and pitfalls, and discuss possible ways to mitigate them.
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Affiliation(s)
- Eli Eisenberg
- Raymond and Beverly Sackler School of Physics and Astronomy, Tel Aviv University, Tel Aviv, Israel.
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22
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Shah S, Yu S, Zhang C, Ali I, Wang X, Qian Y, Xiao T. Retrotransposon SINEs in age-related diseases: Mechanisms and therapeutic implications. Ageing Res Rev 2024; 101:102539. [PMID: 39395576 DOI: 10.1016/j.arr.2024.102539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 09/27/2024] [Accepted: 10/03/2024] [Indexed: 10/14/2024]
Abstract
Retrotransposons are self-replicating genomic elements that move from one genomic location to another using a "copy-and-paste" method involving RNA intermediaries. One family of retrotransposon that has garnered considerable attention for its association with age-related diseases and anti-aging interventions is the short interspersed nuclear elements (SINEs). This review summarizes current knowledge on the roles of SINEs in aging processes and therapies. To underscore the significant research on the involvement of SINEs in aging-related diseases, we commence by outlining compelling evidence on the classification and mechanism, highlighting implications in age-related phenomena. The intricate relationship between SINEs and diseases such as neurodegenerative disorders, heart failure, high blood pressure, atherosclerosis, type 2 diabetes mellitus, osteoporosis, visual system dysfunctions, and cancer is explored, emphasizing their roles in various age-related diseases. Recent investigations into the anti-aging potential of SINE-targeted treatments are examined, with particular attention to how SINE antisense RNA mitigate age-related alterations at the cellular and molecular levels, offering insights into potential therapeutic targets for age-related pathologies. This review aims to compile the most recent advances on the multifaceted roles of SINE retrotransposons in age-related diseases and anti-aging interventions, providing valuable insights into underlying mechanisms and therapeutic avenues for promoting healthy aging.
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Affiliation(s)
- Suleman Shah
- Thoracic Surgery Department of the First Affiliated Hospital, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Cell Biology and Genetics, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen 518055, China
| | - Siyi Yu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Chen Zhang
- Department of Thoracic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning 530021, China
| | - Ilyas Ali
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen 518055, China
| | - Xiufang Wang
- Department of Genetics, Hebei Medical University, Hebei Key Lab of Laboratory Animal, Shijiazhuang 050017, China
| | - Youhui Qian
- Thoracic Surgery Department of the First Affiliated Hospital, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Cell Biology and Genetics, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
| | - Tian Xiao
- Thoracic Surgery Department of the First Affiliated Hospital, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Cell Biology and Genetics, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
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23
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Valentine A, Bosart K, Bush W, Bouley RA, Petreaca RC. Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers. Cancer Genet 2024; 288-289:82-91. [PMID: 39488870 DOI: 10.1016/j.cancergen.2024.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/22/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024]
Abstract
ADAR1 (Adenosine deaminase action on RNA1) is involved in post-transcriptional RNA editing. ADAR1 mutations have been identified in many cancers but its role in tumor formation is still not well understood. Here we used available cancer genomes deposited on CSOMIC and cBioPortal to identify and characterize mutations and changes in ADAR1 expression in cancer cells. We identify several high frequency substitutions including one at R767 which is located in one of the dsRNA interacting domains. In silico protein structure analysis suggest the R767 mutations affect the protein stability and are likely to destabilize interaction with dsRNA. Gene expression analysis shows that in samples with under-expressed ADAR1, there is a statistically significant increase in expression of BLCAP (Bladder Cancer Associated Protein). Although BLCAP was initially identified in bladder cancers, more recent evidence shows that it is a tumor suppressor and BLCAP mutations have been detected in many cancer cells. Epistatic analysis using the cBioPortal mutual exclusivity calculator for the TCGA pan-cancer data shows that co-mutations between ADAR1 and other genes regulated by it are likely in cancer cells except for PTEN, AKT1 and BLCAP. This suggests that when ADAR1 function is impaired, PTEN, AKT1 and BLCAP become essential for survival of cancer cells. We also identified several samples with high mutation burden between ADAR1 and other genes regulated primarily in endometrial cancers. Finally, we show that the deaminase domain is highly conserved in metazoans and mutations within conserved residues do occur in human cancers suggesting that destabilization of the enzyme function is contributing to cancer development.
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Affiliation(s)
- Anna Valentine
- Biology Program, The Ohio State University, Marion, United States
| | - Korey Bosart
- Cancer Biology, The James Comprehensive Cancer Center, OSU, United States
| | - Wesley Bush
- Biology Program, The Ohio State University, Marion, United States; Cancer Biology, The James Comprehensive Cancer Center, OSU, United States
| | - Renee A Bouley
- Department of Chemistry and Biochemistry, The Ohio State University, United States
| | - Ruben C Petreaca
- Cancer Biology, The James Comprehensive Cancer Center, OSU, United States; Department of Molecular Genetics, The Ohio State University, United States.
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24
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Torkler P, Sauer M, Schwartz U, Corbacioglu S, Sommer G, Heise T. LoDEI: a robust and sensitive tool to detect transcriptome-wide differential A-to-I editing in RNA-seq data. Nat Commun 2024; 15:9121. [PMID: 39443485 PMCID: PMC11500352 DOI: 10.1038/s41467-024-53298-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
RNA editing is a highly conserved process. Adenosine deaminase acting on RNA (ADAR) mediated deamination of adenosine (A-to-I editing) is associated with human disease and immune checkpoint control. Functional implications of A-to-I editing are currently of broad interest to academic and industrial research as underscored by the fast-growing number of clinical studies applying base editors as therapeutic tools. Analyzing the dynamics of A-to-I editing, in a biological or therapeutic context, requires the sensitive detection of differential A-to-I editing, a currently unmet need. We introduce the local differential editing index (LoDEI) to detect differential A-to-I editing in RNA-seq datasets using a sliding-window approach coupled with an empirical q value calculation that detects more A-to-I editing sites at the same false-discovery rate compared to existing methods. LoDEI is validated on known and novel datasets revealing that the oncogene MYCN increases and that a specific small non-coding RNA reduces A-to-I editing.
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Affiliation(s)
- Phillipp Torkler
- Faculty of Computer Science, Deggendorf Institute of Technology, Dieter-Görlitz-Platz 1, Deggendorf, 94469, Bavaria, Germany
| | - Marina Sauer
- Department for Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, Regensbug, 93053, Bavaria, Germany
| | - Uwe Schwartz
- NGS Analysis Center, University of Regensburg, Universitätsstraße 31, Regensburg, 93053, Bavaria, Germany
| | - Selim Corbacioglu
- Department for Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, Regensbug, 93053, Bavaria, Germany
| | - Gunhild Sommer
- Department for Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, Regensbug, 93053, Bavaria, Germany
| | - Tilman Heise
- Department for Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, Regensbug, 93053, Bavaria, Germany.
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25
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Kaur R, Nikkel DJ, Wetmore SD. Mechanism of Nucleic Acid Phosphodiester Bond Cleavage by Human Endonuclease V: MD and QM/MM Calculations Reveal a Versatile Metal Dependence. J Phys Chem B 2024; 128:9455-9469. [PMID: 39359137 DOI: 10.1021/acs.jpcb.4c05846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Human endonuclease V (EndoV) catalytically removes deaminated nucleobases by cleaving the phosphodiester bond as part of RNA metabolism. Despite being implicated in several diseases (cancers, cardiovascular diseases, and neurological disorders) and potentially being a useful tool in biotechnology, details of the human EndoV catalytic pathway remain unclear due to limited experimental information beyond a crystal structure of the apoenzyme and select mutational data. Since a mechanistic understanding is critical for further deciphering the central roles and expanding applications of human EndoV in medicine and biotechnology, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations were used to unveil the atomistic details of the catalytic pathway. Due to controversies surrounding the number of metals required for nuclease activity, enzyme-substrate models with different numbers of active site metals and various metal-substrate binding configurations were built based on structural data for other nucleases. Subsequent MD simulations revealed the structure and stability of the human EndoV-substrate complex for a range of active site metal binding architectures. Four unique pathways were then characterized using QM/MM that vary in metal number (one versus two) and modes of substrate coordination [direct versus indirect (water-mediated)], with several mechanisms being fully consistent with experimental structural, kinetic, and mutational data for related nucleases, including members of the EndoV family. Beyond uncovering key roles for several active site amino acids (D240 and K155), our calculations highlight that while one metal is essential for human EndoV activity, the enzyme can benefit from using two metals due to the presence of two suitable metal binding sites. By directly comparing one- versus two-metal-mediated P-O bond cleavage reactions within the confines of the same active site, our work brings a fresh perspective to the "number of metals" controversy.
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Affiliation(s)
- Rajwinder Kaur
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge T1K 3M4, Alberta, Canada
| | - Dylan J Nikkel
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge T1K 3M4, Alberta, Canada
| | - Stacey D Wetmore
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge T1K 3M4, Alberta, Canada
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26
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Yin C, Zhang MM, Wang GL, Deng XY, Tu Z, Jiang SS, Gao ZD, Hao M, Chen Y, Li Y, Yang SY. Loss of ADAR1 induces ferroptosis of breast cancer cells. Cell Signal 2024; 121:111258. [PMID: 38866351 DOI: 10.1016/j.cellsig.2024.111258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/31/2024] [Accepted: 06/09/2024] [Indexed: 06/14/2024]
Abstract
Adenosine deaminases acting on RNA 1(ADAR1), an RNA editing enzyme that converts adenosine to inosine by deamination in double-stranded RNAs, plays an important role in occurrence and progression of various types of cancer. Ferroptosis has emerged as a hot topic of cancer research in recent years. We have previously reported that ADAR1 promotes breast cancer progression by regulating miR-335-5p and METTL3. However, whether ADAR1 has effects on ferroptosis in breast cancer cells is largely unknown. In this study, we knocked down ADAR1 using CRISPR-Cas9 technology or over-expressed ADAR1 protein using plasmid expressing ADAR1 in MCF-7 and MDA-MB-231 breast cancer cell lines, then detected cell viability, and levels of ROS, MDA, GSH, Fe2+, GPX4 protein and miR-335-5p. We showed that the cell proliferation was inhibited, levels of ROS, MDA, Fe2+, and miR-335-5p were increased, while GSH and GPX4 levels were decreased after loss of ADAR1, compared to the control group. The opposite effects were observed after ADAR1 overexpression in the cells. Further, we demonstrated that ADAR1-controlled miR-335-5p targeted Sp1 transcription factor of GPX4, a known ferroptosis molecular marker, leading to inhibition of ferroptosis by ADAR1 in breast cancer cells. Moreover, RNA editing activity of ADAR1 is not essential for inducing ferroptosis. Collectively, loss of ADAR1 induces ferroptosis in breast cancer cells by regulating miR-335-5p/Sp1/GPX4 pathway. The findings may provide insights into the mechanism by which ADAR1 promotes breast cancer progression via inhibiting ferroptosis.
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Affiliation(s)
- Chuan Yin
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Meng-Meng Zhang
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Guo-Liang Wang
- Department of General Surgery, Union Hospital of Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiao-Yan Deng
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Zeng Tu
- Department of Pathogen Biology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Shan-Shan Jiang
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Zheng-Dan Gao
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Meng Hao
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yong Chen
- Department of Radiology and Intervention, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
| | - Yi Li
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
| | - Sheng-Yong Yang
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
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27
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Liu D, Liu Z, Xia Y, Wang Z, Song J, Yu DJ. TransC-ac4C: Identification of N4-Acetylcytidine (ac4C) Sites in mRNA Using Deep Learning. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2024; 21:1403-1412. [PMID: 38607721 DOI: 10.1109/tcbb.2024.3386972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/14/2024]
Abstract
N4-acetylcytidine (ac4C) is a post-transcriptional modification in mRNA that is critical in mRNA translation in terms of stability and regulation. In the past few years, numerous approaches employing convolutional neural networks (CNN) and Transformer have been proposed for the identification of ac4C sites, with each variety of approaches processing distinct characteristics. CNN-based methods excel at extracting local features and positional information, whereas Transformer-based ones stands out in establishing long-range dependencies and generating global representations. Given the importance of both local and global features in mRNA ac4C sites identification, we propose a novel method termed TransC-ac4C which combines CNN and Transformer together for enhancing the feature extraction capability and improving the identification accuracy. Five different feature encoding strategies (One-hot, NCP, ND, EIIP, and K-mer) are employed to generate the mRNA sequence representations, in which way the sequence attributes and physical and chemical properties of the sequences can be embedded. To strengthen the relevance of features, we construct a novel feature fusion method. Firstly, the CNN is employed to process five single features, stitch them together and feed them to the Transformer layer. Then, our approach employs CNN to extract local features and Transformer subsequently to establish global long-range dependencies among extracted features. We use 5-fold cross-validation to evaluate the model, and the evaluation indicators are significantly improved. The prediction accuracy of the two datasets is as high as 81.42% and 80.69%, respectively. It demonstrates the stronger competitiveness and generalization performance of our model.
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28
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Wang ZY, Ge LP, Ouyang Y, Jin X, Jiang YZ. Targeting transposable elements in cancer: developments and opportunities. Biochim Biophys Acta Rev Cancer 2024; 1879:189143. [PMID: 38936517 DOI: 10.1016/j.bbcan.2024.189143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 05/23/2024] [Accepted: 06/19/2024] [Indexed: 06/29/2024]
Abstract
Transposable elements (TEs), comprising nearly 50% of the human genome, have transitioned from being perceived as "genomic junk" to key players in cancer progression. Contemporary research links TE regulatory disruptions with cancer development, underscoring their therapeutic potential. Advances in long-read sequencing, computational analytics, single-cell sequencing, proteomics, and CRISPR-Cas9 technologies have enriched our understanding of TEs' clinical implications, notably their impact on genome architecture, gene regulation, and evolutionary processes. In cancer, TEs, including long interspersed element-1 (LINE-1), Alus, and long terminal repeat (LTR) elements, demonstrate altered patterns, influencing both tumorigenic and tumor-suppressive mechanisms. TE-derived nucleic acids and tumor antigens play critical roles in tumor immunity, bridging innate and adaptive responses. Given their central role in oncology, TE-targeted therapies, particularly through reverse transcriptase inhibitors and epigenetic modulators, represent a novel avenue in cancer treatment. Combining these TE-focused strategies with existing chemotherapy or immunotherapy regimens could enhance efficacy and offer a new dimension in cancer treatment. This review delves into recent TE detection advancements, explores their multifaceted roles in tumorigenesis and immune regulation, discusses emerging diagnostic and therapeutic approaches centered on TEs, and anticipates future directions in cancer research.
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Affiliation(s)
- Zi-Yu Wang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Li-Ping Ge
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yang Ouyang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xi Jin
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yi-Zhou Jiang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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29
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Luo X, Ding H, Zhong Y. RNA editing and glioblastoma: A predictive model based on integrated bioinformatics analysis. Asian J Surg 2024:S1015-9584(24)01755-X. [PMID: 39191589 DOI: 10.1016/j.asjsur.2024.08.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/19/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024] Open
Affiliation(s)
- Xiaobin Luo
- Department of Neurosurgery, Zigong Fourth People's Hospital, Zigong City, Sichuan province, 646000, China
| | - Hao Ding
- Department of Neurosurgery, Zigong Fourth People's Hospital, Zigong City, Sichuan province, 646000, China
| | - Yali Zhong
- Department of Gastroenterology, Zigong First People's Hospital, Zigong City, Sichuan province, 646000, China.
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30
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Hu J, Ning Y, Ma Y, Sun L, Chen G. Characterization of RNA Processing Genes in Colon Cancer for Predicting Clinical Outcomes. Biomark Insights 2024; 19:11772719241258642. [PMID: 39161926 PMCID: PMC11331464 DOI: 10.1177/11772719241258642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/05/2024] [Indexed: 08/21/2024] Open
Abstract
Objective Colon cancer is associated with multiple levels of molecular heterogeneity. RNA processing converts primary transcriptional RNA to mature RNA, which drives tumourigenesis and its maintenance. The characterisation of RNA processing genes in colon cancer urgently needs to be elucidated. Methods In this study, we obtained 1033 relevant samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to explore the heterogeneity of RNA processing phenotypes in colon cancer. Firstly, Unsupervised hierarchical cluster analysis detected 4 subtypes with specific clinical outcomes and biological features via analysis of 485 RNA processing genes. Next, we adopted the least absolute shrinkage and selection operator (LASSO) as well as Cox regression model with penalty to characterise RNA processing-related prognostic features. Results An RNA processing-related prognostic risk model based on 10 genes including FXR1, MFAP1, RBM17, SAGE1, SNRPA1, SRRM4, ADAD1, DDX52, ERI1, and EXOSC7 was identified finally. A composite prognostic nomogram was constructed by combining this feature with the remaining clinical variables including TNM, age, sex, and stage. Genetic variation, pathway activation, and immune heterogeneity with risk signatures were also analysed via bioinformatics methods. The outcomes indicated that the high-risk subgroup was associated with higher genomic instability, increased proliferative and cycle characteristics, decreased tumour killer CD8+ T cells and poorer clinical prognosis than the low-risk group. Conclusion This prognostic classifier based on RNA-edited genes facilitates stratification of colon cancer into specific subgroups according to TNM and clinical outcomes, genetic variation, pathway activation, and immune heterogeneity. It can be used for diagnosis, classification and targeted treatment strategies comparable to current standards in precision medicine. It provides a rationale for elucidation of the role of RNA editing genes and their clinical significance in colon cancer as prognostic markers.
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Affiliation(s)
- Jianwen Hu
- Gastrointestinal Surgery Department, Peking University First Hospital, Beijing, China
- Laboratory Department of Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yingze Ning
- Department of Thoracic Surgery, Peking University Third Hospital, Beijing, China
| | - Yongchen Ma
- Endoscopy Center, Peking University First Hospital, Beijing, PR China
| | - Lie Sun
- Gastrointestinal Surgery Department, Peking University First Hospital, Beijing, China
| | - Guowei Chen
- Gastrointestinal Surgery Department, Peking University First Hospital, Beijing, China
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31
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Li YN, Liang YP, Zhang JQ, Li N, Wei ZY, Rao Y, Chen JH, Jin YY. Dynamic A-to-I RNA editing during acute neuroinflammation in sepsis-associated encephalopathy. Front Neurosci 2024; 18:1435185. [PMID: 39156629 PMCID: PMC11328407 DOI: 10.3389/fnins.2024.1435185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 06/25/2024] [Indexed: 08/20/2024] Open
Abstract
Introduction The activation of cerebral endothelial cells (CECs) has recently been reported to be the earliest acute neuroinflammation event in the CNS during sepsis-associated encephalopathy (SAE). Importantly, adenosine-to-inosine (A-to-I) RNA editing mediated by ADARs has been associated with SAE, yet its role in acute neuroinflammation in SAE remains unclear. Methods Our current study systematically analyzed A-to-I RNA editing in cerebral vessels, cerebral endothelial cells (CECs), and microglia sampled during acute neuroinflammation after treatment in a lipopolysaccharide (LPS)-induced SAE mouse model. Results Our results showed dynamic A-to-I RNA editing activity changes in cerebral vessels during acute neuroinflammation. Differential A-to-I RNA editing (DRE) associated with acute neuroinflammation were identified in these tissue or cells, especially missense editing events such as S367G in antizyme inhibitor 1 (Azin1) and editing events in lincRNAs such as maternally expressed gene 3 (Meg3), AW112010, and macrophage M2 polarization regulator (Mm2pr). Importantly, geranylgeranyl diphosphate synthase 1 (Ggps1) and another three genes were differentially edited across cerebral vessels, CECs, and microglia. Notably, Spearman correlation analysis also revealed dramatic time-dependent DRE during acute neuroinflammation, especially in GTP cyclohydrolase1 (Gch1) and non-coding RNA activated by DNA damage (Norad), both with the editing level positively correlated with both post-LPS treatment time and edited gene expression in cerebral vessels and CECs. Discussion The findings in our current study demonstrate substantial A-to-I RNA editing changes during acute neuroinflammation in SAE, underlining its potential role in the disease.
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Affiliation(s)
- Yu-Ning Li
- School of Biotechnology, Jiangnan University, Wuxi, China
| | - Ya-Ping Liang
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Jing-Qian Zhang
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Na Li
- Wuxi Maternal and Child Healthcare Hospital, Wuxi, Jiangsu, China
| | - Zhi-Yuan Wei
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yijian Rao
- School of Biotechnology, Jiangnan University, Wuxi, China
| | - Jian-Huan Chen
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yun-Yun Jin
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
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32
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Quillin A, Arnould B, Knutson SD, Heemstra JM. Spatial Visualization of A-to-I Editing in Cells Using Endonuclease V Immunostaining Assay (EndoVIA). ACS CENTRAL SCIENCE 2024; 10:1396-1405. [PMID: 39071059 PMCID: PMC11273454 DOI: 10.1021/acscentsci.4c00444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 07/30/2024]
Abstract
Adenosine-to-inosine (A-to-I) editing is one of the most widespread post-transcriptional RNA modifications and is catalyzed by adenosine deaminases acting on RNA (ADARs). Varying across tissue types, A-to-I editing is essential for numerous biological functions, and dysregulation leads to autoimmune and neurological disorders, as well as cancer. Recent evidence has also revealed a link between RNA localization and A-to-I editing, yet understanding of the mechanisms underlying this relationship and its biological impact remains limited. Current methods rely primarily on in vitro characterization of extracted RNA that ultimately erases subcellular localization and cell-to-cell heterogeneity. To address these challenges, we have repurposed endonuclease V (EndoV), a magnesium-dependent ribonuclease that cleaves inosine bases in edited RNA, to selectively bind and detect A-to-I edited RNA in cells. The work herein introduces an endonuclease V immunostaining assay (EndoVIA), a workflow that provides spatial visualization of edited transcripts, enables rapid quantification of overall inosine abundance, and maps the landscape of A-to-I editing within the transcriptome at the nanoscopic level.
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Affiliation(s)
- Alexandria
L. Quillin
- Department
of Chemistry, Washington University in St.
Louis, St. Louis, Missouri 63130, United States
| | - Benoît Arnould
- Department
of Chemistry, Washington University in St.
Louis, St. Louis, Missouri 63130, United States
| | - Steve D. Knutson
- Merck
Center for Catalysis, Princeton University, Princeton, New Jersey 08544, United States
- Department
of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
| | - Jennifer M. Heemstra
- Department
of Chemistry, Washington University in St.
Louis, St. Louis, Missouri 63130, United States
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Chen W, Li S, Huang D, Su Y, Wang J, Liang Z. Identification of prognostic RNA editing profiles for clear cell renal carcinoma. Front Med (Lausanne) 2024; 11:1390803. [PMID: 39091293 PMCID: PMC11291244 DOI: 10.3389/fmed.2024.1390803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
Objective Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer and currently lacks effective biomarkers. This research aims to analyze and identify RNA editing profile associated with ccRCC prognosis through bioinformatics and in vitro experiments. Methods Transcriptome data and clinical information for ccRCC were retrieved from the TCGA database, and RNA editing files were obtained from the Synapse database. Prognostic models were screened, developed, and assessed using consistency index analysis and independent prognostic analysis, etc. Internal validation models were also constructed for further evaluation. Differential genes were investigated using GO, KEGG, and GSEA enrichment analyses. Furthermore, qPCR was performed to determine gene expression in human renal tubular epithelial cells HK-2 and ccRCC cells A-498, 786-O, and Caki-2. Results An RNA editing-based risk score, that effectively distinguishes between high and low-risk populations, has been identified. It includes CHD3| chr17:7815229, MYO19| chr17:34853704, OIP5-AS1| chr15:41590962, MRI1| chr19:13883962, GBP4| chr1:89649327, APOL1| chr22:36662830, FCF1| chr14:75203040 edited sites or genes and could serve as an independent prognostic factor for ccRCC patients. qPCR results showed significant up-regulation of CHD3, MYO19, MRI1, APOL1, and FCF1 in A-498, 786-O, and Caki-2 cells, while the expression of OIP5-AS1 and GBP4 was significantly down-regulated. Conclusion RNA editing site-based prognostic models are valuable in differentiating between high and low-risk populations. The seven identified RNA editing sites may be utilized as potential biomarkers for ccRCC.
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Affiliation(s)
- Weihong Chen
- Department of Anxi County Hospital, Quanzhou, China
| | - Shaobin Li
- Department of Anxi County Hospital, Quanzhou, China
| | | | - Yuchao Su
- Department of Anxi County Hospital, Quanzhou, China
| | - Jing Wang
- Xilin Gol League Central Hospital, Xilin Hot, China
| | - Zhiru Liang
- Xilin Gol League Central Hospital, Xilin Hot, China
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Yang C, Liu Y, Lv C, Xu M, Xu K, Shi J, Tan T, Zhou W, Lv D, Li Y, Xu J, Shao T. CanCellVar: A database for single-cell variants map in human cancer. Am J Hum Genet 2024; 111:1420-1430. [PMID: 38838674 PMCID: PMC11267512 DOI: 10.1016/j.ajhg.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/15/2024] [Accepted: 05/15/2024] [Indexed: 06/07/2024] Open
Abstract
Numerous variants, including both single-nucleotide variants (SNVs) in DNA and A>G RNA edits in mRNA as essential drivers of cellular proliferation and tumorigenesis, are commonly associated with cancer progression and growth. Thus, mining and summarizing single-cell variants will provide a refined and higher-resolution view of cancer and further contribute to precision medicine. Here, we established a database, CanCellVar, which aims to provide and visualize the comprehensive atlas of single-cell variants in tumor microenvironment. The current CanCellVar identified ∼3 million variants (∼1.4 million SNVs and ∼1.4 million A>G RNA edits) involved in 2,754,531 cells of 5 major cell types across 37 cancer types. CanCellVar provides the basic annotation information as well as cellular and molecular function properties of variants. In addition, the clinical relevance of variants can be obtained including tumor grade, treatment, metastasis, and others. Several flexible tools were also developed to aid retrieval and to analyze cell-cell interactions, gene expression, cell-development trajectories, regulation, and molecular structure affected by variants. Collectively, CanCellVar will serve as a valuable resource for investigating the functions and characteristics of single-cell variations and their roles in human tumor evolution and treatment.
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Affiliation(s)
- Changbo Yang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Yujie Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Chongwen Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Mengjia Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Kang Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Jingyi Shi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Tingting Tan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Weiwei Zhou
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Dezhong Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China
| | - Yongsheng Li
- School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin, Heilongjiang Province 150081, China
| | - Juan Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China.
| | - Tingting Shao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province 150001, China.
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Bernal YA, Durán E, Solar I, Sagredo EA, Armisén R. ADAR-Mediated A>I(G) RNA Editing in the Genotoxic Drug Response of Breast Cancer. Int J Mol Sci 2024; 25:7424. [PMID: 39000531 PMCID: PMC11242177 DOI: 10.3390/ijms25137424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/13/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Epitranscriptomics is a field that delves into post-transcriptional changes. Among these modifications, the conversion of adenosine to inosine, traduced as guanosine (A>I(G)), is one of the known RNA-editing mechanisms, catalyzed by ADARs. This type of RNA editing is the most common type of editing in mammals and contributes to biological diversity. Disruption in the A>I(G) RNA-editing balance has been linked to diseases, including several types of cancer. Drug resistance in patients with cancer represents a significant public health concern, contributing to increased mortality rates resulting from therapy non-responsiveness and disease progression, representing the greatest challenge for researchers in this field. The A>I(G) RNA editing is involved in several mechanisms over the immunotherapy and genotoxic drug response and drug resistance. This review investigates the relationship between ADAR1 and specific A>I(G) RNA-edited sites, focusing particularly on breast cancer, and the impact of these sites on DNA damage repair and the immune response over anti-cancer therapy. We address the underlying mechanisms, bioinformatics, and in vitro strategies for the identification and validation of A>I(G) RNA-edited sites. We gathered databases related to A>I(G) RNA editing and cancer and discussed the potential clinical and research implications of understanding A>I(G) RNA-editing patterns. Understanding the intricate role of ADAR1-mediated A>I(G) RNA editing in breast cancer holds significant promise for the development of personalized treatment approaches tailored to individual patients' A>I(G) RNA-editing profiles.
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Affiliation(s)
- Yanara A Bernal
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Eduardo Durán
- Subdepartamento de Genómica y Genética Molecular, Sección Genética Humana, Instituto de Salud Pública de Chile, Avenida Marathon 1000, Ñuñoa, Santiago 7780050, Chile
| | - Isidora Solar
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Eduardo A Sagredo
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77 Stockholm, Sweden
- Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-171 77 Stockholm, Sweden
| | - Ricardo Armisén
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
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Tang AD, Felton C, Hrabeta-Robinson E, Volden R, Vollmers C, Brooks AN. Detecting haplotype-specific transcript variation in long reads with FLAIR2. Genome Biol 2024; 25:173. [PMID: 38956576 PMCID: PMC11218413 DOI: 10.1186/s13059-024-03301-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 06/06/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND RNA-seq has brought forth significant discoveries regarding aberrations in RNA processing, implicating these RNA variants in a variety of diseases. Aberrant splicing and single nucleotide variants (SNVs) in RNA have been demonstrated to alter transcript stability, localization, and function. In particular, the upregulation of ADAR, an enzyme that mediates adenosine-to-inosine editing, has been previously linked to an increase in the invasiveness of lung adenocarcinoma cells and associated with splicing regulation. Despite the functional importance of studying splicing and SNVs, the use of short-read RNA-seq has limited the community's ability to interrogate both forms of RNA variation simultaneously. RESULTS We employ long-read sequencing technology to obtain full-length transcript sequences, elucidating cis-effects of variants on splicing changes at a single molecule level. We develop a computational workflow that augments FLAIR, a tool that calls isoform models expressed in long-read data, to integrate RNA variant calls with the associated isoforms that bear them. We generate nanopore data with high sequence accuracy from H1975 lung adenocarcinoma cells with and without knockdown of ADAR. We apply our workflow to identify key inosine isoform associations to help clarify the prominence of ADAR in tumorigenesis. CONCLUSIONS Ultimately, we find that a long-read approach provides valuable insight toward characterizing the relationship between RNA variants and splicing patterns.
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Affiliation(s)
- Alison D Tang
- Department of Biomolecular Engineering, University of California, Santa Cruz, USA
| | - Colette Felton
- Department of Biomolecular Engineering, University of California, Santa Cruz, USA
| | - Eva Hrabeta-Robinson
- Department of Biomolecular Engineering, University of California, Santa Cruz, USA
| | - Roger Volden
- Department of Biomolecular Engineering, University of California, Santa Cruz, USA
| | - Christopher Vollmers
- Department of Biomolecular Engineering, University of California, Santa Cruz, USA
| | - Angela N Brooks
- Department of Biomolecular Engineering, University of California, Santa Cruz, USA.
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Chen C, Bundschuh R. A-to-I Editing Is Subtype-Specific in Non-Hodgkin Lymphomas. Genes (Basel) 2024; 15:864. [PMID: 39062643 PMCID: PMC11276283 DOI: 10.3390/genes15070864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Cancer is a complex and heterogeneous disease, in which a number of genetic and epigenetic changes occur in tumor onset and progression. Recent studies indicate that changes at the RNA level are also involved in tumorigenesis, such as adenosine-to-inosine (A-to-I) RNA editing. Here, we systematically investigate transcriptome-wide A-to-I editing events in a large number of samples from Non-Hodgkin lymphomas (NHLs). Using a computational pipeline that determines significant differences in editing level between NHL and normal samples at known A-to-I editing sites, we identify a number of differentially edited editing sites between NHL subtypes and normal samples. Most of the differentially edited sites are located in non-coding regions, and many such sites show a strong correlation between gene expression level and editing efficiency, indicating that RNA editing might have direct consequences for the cancer cell's aberrant gene regulation status in these cases. Moreover, we establish a strong link between RNA editing and NHL by demonstrating that NHL and normal samples and even NHL subtypes can be distinguished based on genome-wide RNA editing profiles alone. Our study establishes a strong link between RNA editing, cancer and aberrant gene regulation in NHL.
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Affiliation(s)
- Cai Chen
- Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
- Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA
| | - Ralf Bundschuh
- Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
- Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA
- Department of Physics, The Ohio State University, Columbus, OH 43210, USA
- Department of Chemistry & Biochemistry, The Ohio State University, Columbus, OH 43210, USA
- Division of Hematology, The Ohio State University, Columbus, OH 43210, USA
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Zhu T, Li Q, Zhang Z, Shi J, Li Y, Zhang F, Li L, Song X, Shen J, Jia R. ARID1A loss promotes RNA editing of CDK13 in an ADAR1-dependent manner. BMC Biol 2024; 22:132. [PMID: 38835016 PMCID: PMC11151582 DOI: 10.1186/s12915-024-01927-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 05/22/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to play a significant role both in tumor suppression and tumor initiation, which is highly dependent upon context. Previous studies have suggested that ARID1A deficiency may contribute to cancer development. The specific mechanisms of whether ARID1A loss affects tumorigenesis by RNA editing remain unclear. RESULTS Our findings indicate that the deficiency of ARID1A leads to an increase in RNA editing levels and alterations in RNA editing categories mediated by adenosine deaminases acting on RNA 1 (ADAR1). ADAR1 edits the CDK13 gene at two previously unidentified sites, namely Q113R and K117R. Given the crucial role of CDK13 as a cyclin-dependent kinase, we further observed that ADAR1 deficiency results in changes in the cell cycle. Importantly, the sensitivity of ARID1A-deficient tumor cells to SR-4835, a CDK12/CDK13 inhibitor, suggests a promising therapeutic approach for individuals with ARID1A-mutant tumors. Knockdown of ADAR1 restored the sensitivity of ARID1A deficient cells to SR-4835 treatment. CONCLUSIONS ARID1A deficiency promotes RNA editing of CDK13 by regulating ADAR1.
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Affiliation(s)
- Tianyu Zhu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Qian Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Zhe Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Jiahao Shi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Yongyun Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Feng Zhang
- Department of Histoembryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Lingjie Li
- Department of Histoembryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Xin Song
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China.
| | - Jianfeng Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China.
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China.
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Huang E, Frydman C, Xiao X. Navigating the landscape of epitranscriptomics and host immunity. Genome Res 2024; 34:515-529. [PMID: 38702197 PMCID: PMC11146601 DOI: 10.1101/gr.278412.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2024]
Abstract
RNA modifications, also termed epitranscriptomic marks, encompass chemical alterations to individual nucleotides, including processes such as methylation and editing. These marks contribute to a wide range of biological processes, many of which are related to host immune system defense. The functions of immune-related RNA modifications can be categorized into three main groups: regulation of immunogenic RNAs, control of genes involved in innate immune response, and facilitation of adaptive immunity. Here, we provide an overview of recent research findings that elucidate the contributions of RNA modifications to each of these processes. We also discuss relevant methods for genome-wide identification of RNA modifications and their immunogenic substrates. Finally, we highlight recent advances in cancer immunotherapies that aim to reduce cancer cell viability by targeting the enzymes responsible for RNA modifications. Our presentation of these dynamic research avenues sets the stage for future investigations in this field.
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Affiliation(s)
- Elaine Huang
- Bioinformatics Interdepartmental Program, University of California, Los Angeles, California 90095, USA
| | - Clara Frydman
- Bioinformatics Interdepartmental Program, University of California, Los Angeles, California 90095, USA
| | - Xinshu Xiao
- Bioinformatics Interdepartmental Program, University of California, Los Angeles, California 90095, USA;
- Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA
- Molecular Biology Interdepartmental Program, University of California, Los Angeles, California 90095, USA
- Molecular Biology Institute, University of California, Los Angeles, California 90095, USA
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40
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Zhu Z, Lu J. Development and assessment of an RNA editing-based risk model for the prognosis of cervical cancer patients. Medicine (Baltimore) 2024; 103:e38116. [PMID: 38728474 PMCID: PMC11081546 DOI: 10.1097/md.0000000000038116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/12/2024] [Indexed: 05/12/2024] Open
Abstract
RNA editing, as an epigenetic mechanism, exhibits a strong correlation with the occurrence and development of cancers. Nevertheless, few studies have been conducted to investigate the impact of RNA editing on cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). In order to study the connection between RNA editing and CESC patients' prognoses, we obtained CESC-related information from The Cancer Genome Atlas (TCGA) database and randomly allocated the patients into the training group or testing group. An RNA editing-based risk model for CESC patients was established by Cox regression analysis and least absolute shrinkage and selection operator (LASSO). According to the median score generated by this RNA editing-based risk model, patients were categorized into subgroups with high and low risks. We further constructed the nomogram by risk scores and clinical characteristics and analyzed the impact of RNA editing levels on host gene expression levels and adenosine deaminase acting on RNA. Finally, we also compared the biological functions and pathways of differentially expressed genes (DEGs) between different subgroups by enrichment analysis. In this risk model, we screened out 6 RNA editing sites with significant prognostic value. The constructed nomogram performed well in forecasting patients' prognoses. Furthermore, the level of RNA editing at the prognostic site exhibited a strong correlation with host gene expression. In the high-risk subgroup, we observed multiple biological functions and pathways associated with immune response, cell proliferation, and tumor progression. This study establishes an RNA editing-based risk model that helps forecast patients' prognoses and offers a new understanding of the underlying mechanism of RNA editing in CESC.
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Affiliation(s)
- Zihan Zhu
- Department of Biostatistics, School of Public Health, Nanjing Medical University 101 Longmian Avenue, Nanjing, P.R. China
| | - Jing Lu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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41
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Van Norden M, Falls Z, Mandloi S, Segal BH, Baysal BE, Samudrala R, Elkin PL. The implications of APOBEC3-mediated C-to-U RNA editing for human disease. Commun Biol 2024; 7:529. [PMID: 38704509 PMCID: PMC11069577 DOI: 10.1038/s42003-024-06239-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 04/24/2024] [Indexed: 05/06/2024] Open
Abstract
Intra-organism biodiversity is thought to arise from epigenetic modification of constituent genes and post-translational modifications of translated proteins. Here, we show that post-transcriptional modifications, like RNA editing, may also contribute. RNA editing enzymes APOBEC3A and APOBEC3G catalyze the deamination of cytosine to uracil. RNAsee (RNA site editing evaluation) is a computational tool developed to predict the cytosines edited by these enzymes. We find that 4.5% of non-synonymous DNA single nucleotide polymorphisms that result in cytosine to uracil changes in RNA are probable sites for APOBEC3A/G RNA editing; the variant proteins created by such polymorphisms may also result from transient RNA editing. These polymorphisms are associated with over 20% of Medical Subject Headings across ten categories of disease, including nutritional and metabolic, neoplastic, cardiovascular, and nervous system diseases. Because RNA editing is transient and not organism-wide, future work is necessary to confirm the extent and effects of such editing in humans.
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Affiliation(s)
- Melissa Van Norden
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Zackary Falls
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Sapan Mandloi
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Brahm H Segal
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Bora E Baysal
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Ram Samudrala
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Peter L Elkin
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
- Department of Veterans Affairs, VA Western New York Healthcare System, Buffalo, NY, USA.
- Faculty of Engineering, University of Southern Denmark, Odense, Denmark.
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42
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Fadra N, Schultz-Rogers LE, Chanana P, Cousin MA, Macke EL, Ferrer A, Pinto E Vairo F, Olson RJ, Oliver GR, Mulvihill LA, Jenkinson G, Klee EW. Identification of skewed X chromosome inactivation using exome and transcriptome sequencing in patients with suspected rare genetic disease. BMC Genomics 2024; 25:371. [PMID: 38627676 PMCID: PMC11020449 DOI: 10.1186/s12864-024-10240-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 03/18/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND X-chromosome inactivation (XCI) is an epigenetic process that occurs during early development in mammalian females by randomly silencing one of two copies of the X chromosome in each cell. The preferential inactivation of either the maternal or paternal copy of the X chromosome in a majority of cells results in a skewed or non-random pattern of X inactivation and is observed in over 25% of adult females. Identifying skewed X inactivation is of clinical significance in patients with suspected rare genetic diseases due to the possibility of biased expression of disease-causing genes present on the active X chromosome. The current clinical test for the detection of skewed XCI relies on the methylation status of the methylation-sensitive restriction enzyme (Hpall) binding site present in proximity of short tandem polymorphic repeats on the androgen receptor (AR) gene. This approach using one locus results in uninformative or inconclusive data for 10-20% of tests. Further, recent studies have shown inconsistency between methylation of the AR locus and the state of inactivation of the X chromosome. Herein, we develop a method for estimating X inactivation status, using exome and transcriptome sequencing data derived from blood in 227 female samples. We built a reference model for evaluation of XCI in 135 females from the GTEx consortium. We tested and validated the model on 11 female individuals with different types of undiagnosed rare genetic disorders who were clinically tested for X-skew using the AR gene assay and compared results to our outlier-based analysis technique. RESULTS In comparison to the AR clinical test for identification of X inactivation, our method was concordant with the AR method in 9 samples, discordant in 1, and provided a measure of X inactivation in 1 sample with uninformative clinical results. We applied this method on an additional 81 females presenting to the clinic with phenotypes consistent with different hereditary disorders without a known genetic diagnosis. CONCLUSIONS This study presents the use of transcriptome and exome sequencing data to provide an accurate and complete estimation of X-inactivation and skew status in a cohort of female patients with different types of suspected rare genetic disease.
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Affiliation(s)
- Numrah Fadra
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Laura E Schultz-Rogers
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Pritha Chanana
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Margot A Cousin
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Erica L Macke
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Alejandro Ferrer
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Filippo Pinto E Vairo
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Rory J Olson
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Gavin R Oliver
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Lindsay A Mulvihill
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Garrett Jenkinson
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
| | - Eric W Klee
- Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
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Nishimura K, Saika W, Inoue D. Minor introns impact on hematopoietic malignancies. Exp Hematol 2024; 132:104173. [PMID: 38309573 DOI: 10.1016/j.exphem.2024.104173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/25/2023] [Accepted: 01/03/2024] [Indexed: 02/05/2024]
Abstract
In the intricate orchestration of the central dogma, pre-mRNA splicing plays a crucial role in the post-transcriptional process that transforms DNA into mature mRNA. Widely acknowledged as a pivotal RNA processing step, it significantly influences gene expression and alters the functionality of gene product proteins. Although U2-dependent spliceosomes efficiently manage the removal of over 99% of introns, a distinct subset of essential genes undergo splicing with a different intron type, denoted as minor introns, using U12-dependent spliceosomes. Mutations in spliceosome component genes are now recognized as prevalent genetic abnormalities in cancer patients, especially those with hematologic malignancies. Despite the relative rarity of minor introns, genes containing them are evolutionarily conserved and play crucial roles in functions such as the RAS-MAPK pathway. Disruptions in U12-type minor intron splicing caused by mutations in snRNA or its regulatory components significantly contribute to cancer progression. Notably, recurrent mutations associated with myelodysplastic syndrome (MDS) in the minor spliceosome component ZRSR2 underscore its significance. Examination of ZRSR2-mutated MDS cells has revealed that only a subset of minor spliceosome-dependent genes, such as LZTR1, consistently exhibit missplicing. Recent technological advancements have uncovered insights into minor introns, raising inquiries beyond current understanding. This review comprehensively explores the importance of minor intron regulation, the molecular implications of minor (U12-type) spliceosomal mutations and cis-regulatory regions, and the evolutionary progress of studies on minor, aiming to provide a sophisticated understanding of their intricate role in cancer biology.
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Affiliation(s)
- Koutarou Nishimura
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan.
| | - Wataru Saika
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan; Department of Hematology, Shiga University of Medical Science, Ōtsu, Shiga, Japan
| | - Daichi Inoue
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan.
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Bernal YA, Blanco A, Sagredo EA, Oróstica K, Alfaro I, Marcelain K, Armisén R. A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer. Biomedicines 2024; 12:728. [PMID: 38672084 PMCID: PMC11048297 DOI: 10.3390/biomedicines12040728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 04/28/2024] Open
Abstract
Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.
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Affiliation(s)
- Yanara A. Bernal
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610658, Chile; (Y.A.B.); (A.B.); (I.A.)
| | - Alejandro Blanco
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610658, Chile; (Y.A.B.); (A.B.); (I.A.)
| | - Eduardo A. Sagredo
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrhenius väg 20C, SE-106 91 Stockholm, Sweden;
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
- Science for Life Laboratory, SE-171 65 Solna, Sweden
| | - Karen Oróstica
- Instituto de Investigación Interdisciplinaria, Vicerrectoría Académica, Universidad de Talca, Talca 3460000, Chile;
| | - Ivan Alfaro
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610658, Chile; (Y.A.B.); (A.B.); (I.A.)
| | - Katherine Marcelain
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
- Centro de Prevención y Control de Cáncer (CECAN), Universidad de Chile, Santiago 8380453, Chile
| | - Ricardo Armisén
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610658, Chile; (Y.A.B.); (A.B.); (I.A.)
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Quillin AL, Arnould B, Knutson SD, Heemstra JM. Spatial visualization of A-to-I Editing in cells using Endonuclease V Immunostaining Assay (EndoVIA). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.04.583344. [PMID: 38496620 PMCID: PMC10942280 DOI: 10.1101/2024.03.04.583344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Adenosine-to-Inosine (A-to-I) editing is one of the most widespread post-transcriptional RNA modifications and is catalyzed by adenosine deaminases acting on RNA (ADARs). Varying across tissue types, A-to-I editing is essential for numerous biological functions and dysregulation leads to autoimmune and neurological disorders, as well as cancer. Recent evidence has also revealed a link between RNA localization and A-to-I editing, yet understanding of the mechanisms underlying this relationship and its biological impact remains limited. Current methods rely primarily on in vitro characterization of extracted RNA that ultimately erases subcellular localization and cell-to-cell heterogeneity. To address these challenges, we have repurposed Endonuclease V (EndoV), a magnesium dependent ribonuclease that cleaves inosine bases in edited RNA, to selectively bind and detect A-to-I edited RNA in cells. The work herein introduces Endonuclease V Immunostaining Assay (EndoVIA), a workflow that provides spatial visualization of edited transcripts, enables rapid quantification of overall inosine abundance, and maps the landscape of A-to-I editing within the transcriptome at the nanoscopic level.
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46
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Levanon EY, Cohen-Fultheim R, Eisenberg E. In search of critical dsRNA targets of ADAR1. Trends Genet 2024; 40:250-259. [PMID: 38160061 DOI: 10.1016/j.tig.2023.12.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/04/2023] [Accepted: 12/04/2023] [Indexed: 01/03/2024]
Abstract
Recent studies have underscored the pivotal role of adenosine-to-inosine RNA editing, catalyzed by ADAR1, in suppressing innate immune interferon responses triggered by cellular double-stranded RNA (dsRNA). However, the specific ADAR1 editing targets crucial for this regulatory function remain elusive. We review analyses of transcriptome-wide ADAR1 editing patterns and their evolutionary dynamics, which offer valuable insights into this unresolved query. The growing appreciation of the significance of immunogenic dsRNAs and their editing in inflammatory and autoimmune diseases and cancer calls for a more comprehensive understanding of dsRNA immunogenicity, which may promote our understanding of these diseases and open doors to therapeutic avenues.
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Affiliation(s)
- Erez Y Levanon
- Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel.
| | - Roni Cohen-Fultheim
- Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Eli Eisenberg
- Raymond and Beverly Sackler School of Physics and Astronomy, Tel Aviv, University, Tel Aviv 6997801, Israel.
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47
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Rivera M, Zhang H, Pham J, Isquith J, Zhou QJ, Balaian L, Sasik R, Enlund S, Mark A, Ma W, Holm F, Fisch KM, Kuo DJ, Jamieson C, Jiang Q. Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing. Cell Rep 2024; 43:113704. [PMID: 38265938 PMCID: PMC10962356 DOI: 10.1016/j.celrep.2024.113704] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 10/24/2023] [Accepted: 01/09/2024] [Indexed: 01/26/2024] Open
Abstract
Leukemia-initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches. Here, we show that the RNA-editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine editing is a common attribute of relapsed T cell acute lymphoblastic leukemia (T-ALL) regardless of molecular subtype. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL patient-derived xenograft models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor melanoma differentiation-associated protein 5 (MDA5). Moreover, we uncover that the cell-intrinsic level of MDA5 dictates the dependency on the ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.
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Affiliation(s)
- Maria Rivera
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
| | - Haoran Zhang
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
| | - Jessica Pham
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jane Isquith
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Qingchen Jenny Zhou
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
| | - Larisa Balaian
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Roman Sasik
- Center for Computational Biology & Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92093-0681, USA
| | - Sabina Enlund
- Department of Women's and Children's Health, Division of Pediatric Oncology and Pediatric Surgery, Karolinska Institutet, Solna, Sweden
| | - Adam Mark
- Center for Computational Biology & Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92093-0681, USA
| | - Wenxue Ma
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Frida Holm
- Department of Women's and Children's Health, Division of Pediatric Oncology and Pediatric Surgery, Karolinska Institutet, Solna, Sweden
| | - Kathleen M Fisch
- Center for Computational Biology & Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92093-0681, USA; Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Diego, La Jolla, CA 92037, USA
| | - Dennis John Kuo
- Moores Cancer Center, La Jolla, CA 92037, USA; Division of Pediatric Hematology-Oncology, Rady Children's Hospital San Diego, University of California, San Diego, San Diego, CA 92123, USA
| | - Catriona Jamieson
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
| | - Qingfei Jiang
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA.
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Xu J, He J, Yang J, Wang F, Huo Y, Guo Y, Si Y, Gao Y, Wang F, Cheng H, Cheng T, Yu J, Wang X, Ma Y. REDH: A database of RNA editome in hematopoietic differentiation and malignancy. Chin Med J (Engl) 2024; 137:283-293. [PMID: 37386732 PMCID: PMC10836905 DOI: 10.1097/cm9.0000000000002782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking. METHODS We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases. RESULTS We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control. CONCLUSIONS REDH is accessible at http://www.redhdatabase.com/ . This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.
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Affiliation(s)
- Jiayue Xu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Jiahuan He
- Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Jiabin Yang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
- Department of Biochemistry and Molecular Biology, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Fengjiao Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China
| | - Yue Huo
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yuehong Guo
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yanmin Si
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yufeng Gao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Fang Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Hui Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China
| | - Jia Yu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, Sichuan 610052, China
| | - Xiaoshuang Wang
- Department of Biochemistry and Molecular Biology, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Yanni Ma
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
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Li W, Wu H, Li J, Wang Z, Cai M, Liu X, Liu G. Transcriptomic analysis reveals associations of blood-based A-to-I editing with Parkinson's disease. J Neurol 2024; 271:976-985. [PMID: 37902879 DOI: 10.1007/s00415-023-12053-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 10/07/2023] [Accepted: 10/09/2023] [Indexed: 11/01/2023]
Abstract
BACKGROUND Adenosine-to-inosine (A-to-I) editing is the most common type of RNA editing in humans and the role of A-to-I RNA editing remains unclear in Parkinson's disease (PD). OBJECTIVE We aimed to explore the potential causal association between A-to-I editing and PD, and to assess whether changes in A-to-I editing were associated with cognitive progression in PD. METHODS The RNA-seq data from 380 PD patients and 178 healthy controls in the Parkinson's Progression Marker Initiative cohort was used to quantify A-to-I editing sites. We performed cis-RNA editing quantitative trait loci analysis and a two-sample Mendelian Randomization (MR) study by integrating genome-wide association studies to infer the potential causality between A-to-I editing and PD pathogenesis. The potential causal A-to-I editing sites were further confirmed by Summary-data-based MR analysis. Spearman's correlation analysis was performed to characterize the association between longitudinal A-to-I editing and cognitive progression in patients with PD. RESULTS We identified 17 potential causal A-to-I editing sites for PD and indicated that genetic risk variants may contribute to the risk of PD through A-to-I editing. These A-to-I editing sites were located in genes NCOR1, KANSL1 and BST1. Moreover, we observed 57 sites whose longitudinal A-to-I editing levels correlated with cognitive progression in PD. CONCLUSIONS We found potential causal A-to-I editing sites for PD onset and longitudinal changes of A-to-I editing were associated with cognitive progression in PD. We anticipate this study will provide new biological insights and drive the discovery of the epitranscriptomic role underlying Parkinson's disease.
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Affiliation(s)
- Weimin Li
- Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China
- Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Hao Wu
- Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China
- Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Jinxia Li
- Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China
- Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Zhuo Wang
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 518172, Guangdong, People's Republic of China
| | - Miao Cai
- Neurology Department, Zhejiang Hospital, Hangzhou, 310013, People's Republic of China
| | - Xiaoli Liu
- Neurology Department, Zhejiang Hospital, Hangzhou, 310013, People's Republic of China
| | - Ganqiang Liu
- Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China.
- Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, No.66, Gongchang Road, Guangming District, Shenzhen, 518107, Guangdong, People's Republic of China.
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50
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Jiao Y, Xu Y, Liu C, Miao R, Liu C, Wang Y, Liu J. The role of ADAR1 through and beyond its editing activity in cancer. Cell Commun Signal 2024; 22:42. [PMID: 38233935 PMCID: PMC10795376 DOI: 10.1186/s12964-023-01465-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 12/27/2023] [Indexed: 01/19/2024] Open
Abstract
Adenosine-to-inosine (A-to-I) editing of RNA, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, is a prevalent RNA modification in mammals. It has been shown that A-to-I editing plays a critical role in multiple diseases, such as cardiovascular disease, neurological disorder, and particularly cancer. ADARs are the family of enzymes, including ADAR1, ADAR2, and ADAR3, that catalyze the occurrence of A-to-I editing. Notably, A-to-I editing is mainly catalyzed by ADAR1. Given the significance of A-to-I editing in disease development, it is important to unravel the complex roles of ADAR1 in cancer for the development of novel therapeutic interventions.In this review, we briefly describe the progress of research on A-to-I editing and ADARs in cancer, mainly focusing on the role of ADAR1 in cancer from both editing-dependent and independent perspectives. In addition, we also summarized the factors affecting the expression and editing activity of ADAR1 in cancer.
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Affiliation(s)
- Yue Jiao
- School of Basic Medicine Sciences, Weifang Medical University, Weifang, 261053, China
| | - Yuqin Xu
- School of Basic Medicine Sciences, Weifang Medical University, Weifang, 261053, China
| | - Chengbin Liu
- School of Basic Medicine Sciences, Weifang Medical University, Weifang, 261053, China
| | - Rui Miao
- School of Basic Medicine Sciences, Weifang Medical University, Weifang, 261053, China
| | - Chunyan Liu
- School of Basic Medicine Sciences, Weifang Medical University, Weifang, 261053, China
| | - Yilong Wang
- School of Basic Medicine Sciences, Weifang Medical University, Weifang, 261053, China
| | - Jiao Liu
- School of Basic Medicine Sciences, Weifang Medical University, Weifang, 261053, China.
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