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1
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Yang H, Lan L. Transcription-coupled DNA repair protects genome stability upon oxidative stress-derived DNA strand breaks. FEBS Lett 2025; 599:168-176. [PMID: 38813713 PMCID: PMC11607181 DOI: 10.1002/1873-3468.14938] [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: 02/01/2024] [Revised: 03/27/2024] [Accepted: 04/29/2024] [Indexed: 05/31/2024]
Abstract
Elevated oxidative stress, which threatens genome stability, has been detected in almost all types of cancers. Cells employ various DNA repair pathways to cope with DNA damage induced by oxidative stress. Recently, a lot of studies have provided insights into DNA damage response upon oxidative stress, specifically in the context of transcriptionally active genomes. Here, we summarize recent studies to help understand how the transcription is regulated upon DNA double strand breaks (DSB) and how DNA repair pathways are selectively activated at the damage sites coupling with transcription. The role of RNA molecules, especially R-loops and RNA modifications during the DNA repair process, is critical for protecting genome stability. This review provides an update on how cells protect transcribed genome loci via transcription-coupled repair pathways.
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Affiliation(s)
- Haibo Yang
- Department of Urology, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, USA
| | - Li Lan
- Departments of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC, USA
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2
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Wang Y, Yu T, Zhao Z, Li X, Song Y, He Y, Zhou Y, Li P, An L, Wang F. SMAD4 Limits PARP1 dependent DNA Repair to Render Pancreatic Cancer Cells Sensitive to Radiotherapy. Cell Death Dis 2024; 15:818. [PMID: 39528473 PMCID: PMC11555233 DOI: 10.1038/s41419-024-07210-7] [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: 06/10/2024] [Revised: 10/24/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Dysregulation of SMAD4 (i.e. somatic mutation) is strongly associated with poor pancreatic ductal adenocarcinoma (PDAC) prognosis, yet the molecular mechanisms remain underlying this relationship obscure. Previously, we discovered that SMAD4 mutation renders pancreatic cancer resistant to radiotherapy via promotion of autophagy. In the current work, we observed a downregulation of the protein level of SMAD4 in PDAC as compared with adjacent normal tissue, and that such SMAD4low PDAC failed to benefit from chemotherapy. Furthermore, we observed that SMAD4 depletion dramatically enhanced DNA repair capacity in response to irradiation (IR) or a radiomimetic chemical. Interestingly, we found the radiomimetic chemical having induced a robust translocation of SMAD4 into the nucleus, where a direct interaction was shown to occur between the MH1 domain of SMAD4 and the DBD domain of PARP1. Functionally, the SMAD4-PARP1 interaction was found to perturb the recruitment of PARP1 to DNA damage sites. Accordingly, the combination of olaparib and radiotherapy was indicated in vivo and in vitro to specifically reduce the growth of SMAD4-deficient PDAC by attenuating PARP1 activity. Collectively, our results revealed a novel molecular mechanism for the involvement of the SMAD4-PARP1 interaction in DNA repair with a vital role in radiotherapy response in PDAC. Based on our set of findings, our findings offer a new combined therapeutic strategy for SMAD4 deficient PDAC that can significantly reduce pancreatic cancer radiotherapy resistance.
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Affiliation(s)
- Yang Wang
- Department of Gastroenterology, Huadong Hospital, Fudan University, 200040, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072, Shanghai, China
| | - Tianyu Yu
- Department of Gastroenterology, Huadong Hospital, Fudan University, 200040, Shanghai, China
| | - Zhangting Zhao
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072, Shanghai, China
| | - Xiaobing Li
- Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, 200444, Shanghai, China
| | - Yiran Song
- Department of Gastroenterology, Huadong Hospital, Fudan University, 200040, Shanghai, China
| | - Yazhi He
- Department of Gastroenterology, Huadong Hospital, Fudan University, 200040, Shanghai, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072, Shanghai, China.
| | - Pu Li
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Liwei An
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072, Shanghai, China.
| | - Feng Wang
- Department of Gastroenterology, Huadong Hospital, Fudan University, 200040, Shanghai, China.
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3
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Zhao X, Ma Y, Li J, Sun X, Sun Y, Qu F, Shi X, Xie Y, Liu S, Ma Y, Ji C, Hu W, Che S, Zhang X. The AEG-1-USP10-PARP1 axis confers radioresistance in esophageal squamous cell carcinoma via facilitating homologous recombination-dependent DNA damage repair. Cancer Lett 2023; 577:216440. [PMID: 37838281 DOI: 10.1016/j.canlet.2023.216440] [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: 07/04/2023] [Revised: 09/12/2023] [Accepted: 10/05/2023] [Indexed: 10/16/2023]
Abstract
Radiotherapy is the standard adjuvant treatment for esophageal squamous cell carcinoma (ESCC), yet radioresistance remains a major obstacle leading to treatment failure and unfavorable prognosis. Previous reports have demonstrated the involvement of astrocyte elevated gene-1 (AEG-1) in tumorigenesis and progression of multiple malignancies. Nevertheless, the precise role of AEG-1 in the radioresistance of ESCC remains elusive. Here, we unveiled a strong correlation between aberrant AEG-1 gene overexpression and malignant progression as well as adverse prognosis in ESCC patients. Moreover, both in vitro and in vivo investigations revealed that AEG-1 significantly alleviated irradiation-induced DNA damage and enhanced radiation resistance in ESCC cells. Mechanistically, AEG-1 recruited the deubiquitinase USP10 to remove the K48-linked polyubiquitin chains at the Lys425 of PARP1, thus preventing its proteasomal degradation. This orchestrated process facilitated homologous recombination-mediated DNA double-strand breaks (DSBs) repair, culminating in mitigated DNA damage and acquired radioresistance in ESCC cells. Notably, PARP1 overexpression reversed the radiosensitizing effect caused by AEG-1 deficiency. Collectively, these findings shed new light on the mechanism of ESCC radioresistance, providing potential therapeutic targets to enhance the efficacy of radiotherapy in ESCC.
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Affiliation(s)
- Xu Zhao
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Yuan Ma
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Jing Li
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Xuanzi Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Yuchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Fengyi Qu
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Xiaobo Shi
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuchen Xie
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Siqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Yanfang Ma
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Chao Ji
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Weibin Hu
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Shaomin Che
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China.
| | - Xiaozhi Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi, 710061, China.
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4
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Grand RJ. SARS-CoV-2 and the DNA damage response. J Gen Virol 2023; 104:001918. [PMID: 37948194 PMCID: PMC10768691 DOI: 10.1099/jgv.0.001918] [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: 09/01/2023] [Accepted: 10/27/2023] [Indexed: 11/12/2023] Open
Abstract
The recent coronavirus disease 2019 (COVID-19) pandemic was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by respiratory distress, multiorgan dysfunction and, in some cases, death. The virus is also responsible for post-COVID-19 condition (commonly referred to as 'long COVID'). SARS-CoV-2 is a single-stranded, positive-sense RNA virus with a genome of approximately 30 kb, which encodes 26 proteins. It has been reported to affect multiple pathways in infected cells, resulting, in many cases, in the induction of a 'cytokine storm' and cellular senescence. Perhaps because it is an RNA virus, replicating largely in the cytoplasm, the effect of SARS-Cov-2 on genome stability and DNA damage responses (DDRs) has received relatively little attention. However, it is now becoming clear that the virus causes damage to cellular DNA, as shown by the presence of micronuclei, DNA repair foci and increased comet tails in infected cells. This review considers recent evidence indicating how SARS-CoV-2 causes genome instability, deregulates the cell cycle and targets specific components of DDR pathways. The significance of the virus's ability to cause cellular senescence is also considered, as are the implications of genome instability for patients suffering from long COVID.
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Affiliation(s)
- Roger J. Grand
- Institute for Cancer and Genomic Science, The Medical School, University of Birmingham, Birmingham, UK
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Rana I, Nguyen PK, Rigutto G, Louie A, Lee J, Smith MT, Zhang L. Mapping the key characteristics of carcinogens for glyphosate and its formulations: A systematic review. CHEMOSPHERE 2023; 339:139572. [PMID: 37474029 DOI: 10.1016/j.chemosphere.2023.139572] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 07/16/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023]
Abstract
Glyphosate was classified as a probable human carcinogen (Group 2A) by the International Agency for Research on Cancer (IARC) partially due to strong mechanistic evidence in 2015. Since then, numerous studies of glyphosate and its formulations (GBF) have emerged. These studies can be evaluated for cancer hazard identification with the newly described ten key characteristics (KC) of carcinogens approach. Our objective was to assess all in vivo, ex vivo, and in vitro mechanistic studies of human and experimental animals (mammals) that compared exposure to glyphosate/GBF with low/no exposure counterparts for evidence of the ten KCs. A protocol with our methods adhering to PRISMA guidelines was registered a priori (INPLASY202180045). Two blinded reviewers screened all in vivo, ex vivo, and in vitro studies of glyphosate/GBF exposure in humans/mammals reporting any KC-related outcome available in PubMed before August 2021. Studies that met inclusion criteria underwent data extraction conducted in duplicate for each KC outcome reported along with key aspects of internal/external validity, results, and reference information. These data were used to construct a matrix that was subsequently analyzed in the program R to conduct strength of evidence and quality assessments. Of the 2537 articles screened, 175 articles met inclusion criteria, from which we extracted >50,000 data points related to KC outcomes. Data analysis revealed strong evidence for KC2, KC4, KC5, KC6, KC8, limited evidence for KC1 and KC3, and inadequate evidence for KC7, KC9, and KC10. Notably, our in-depth quality analyses of genotoxicity (KC2) and endocrine disruption (KC8) revealed strong and consistent positive findings. For KC2, we found: 1) studies conducted in humans and human cells provided stronger positive evidence than counterpart animal models; 2) GBF elicited a stronger effect in both human and animal systems when compared to glyphosate alone; and 3) the highest quality studies in humans and human cells consistently revealed strong evidence of genotoxicity. Our analysis of KC8 indicated that glyphosate's ability to modulate hormone levels and estrogen receptor activity is sensitive to both exposure concentration and formulation. The modulations observed provide clear evidence that glyphosate interacts with receptors, alters receptor activation, and modulates the levels and effects of endogenous ligands (including hormones). Our findings strengthen the mechanistic evidence that glyphosate is a probable human carcinogen and provide biological plausibility for previously reported cancer associations in humans, such as non-Hodgkin lymphoma. We identified potential molecular interactions and subsequent key events that were used to generate a probable pathway to lymphomagenesis.
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Affiliation(s)
- Iemaan Rana
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States
| | - Patton K Nguyen
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States
| | - Gabrielle Rigutto
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States
| | - Allen Louie
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States
| | - Jane Lee
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States
| | - Martyn T Smith
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States.
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Xu J, Zhang Q, Su Z, Liu Y, Yan T, Zhang Y, Wang T, Wei X, Chen Z, Hu G, Chen T, Jia G. Genetic damage and potential mechanism exploration under different air pollution patterns by multi-omics. ENVIRONMENT INTERNATIONAL 2022; 170:107636. [PMID: 36423397 DOI: 10.1016/j.envint.2022.107636] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/02/2022] [Accepted: 11/14/2022] [Indexed: 06/16/2023]
Abstract
Ambient air pollution was classified as carcinogenic to humans (Group 1) for lung cancer. DNA damage was an important first step in the process of carcinogenesis, and could also be induced by air pollution. In this study, intratracheal instillation and real-time air exposure system were combined to establish SHP (short-term high-level PM2.5) and LLPO (long-term low-level PM2.5 and O3) exposure patterns, respectively. Hierarchical levels of genetic biomarkers were analyzed to explore DNA damage effects in rats. Representative DNA repair genes from different repair pathways were selected to explore the relative expression levels. The methylation level of differentially expressed repair genes were also determined. Besides, miRNA sequencing and non-targeted metabolomic analysis were performed in rat lungs. KEGG and multi-omics analysis were used to explore the potential mechanism of genetic damage under different air pollution patterns. We found that LLPO exposure induced DSBs and chromosome damage. SHP exposure could induce DSBs and DNA oxidative damage, and the effects of genetic damage under this pollution pattern could be repaired by natural repair. Repair genes involved in two pattern were different. SHP exposure could induce higher methylation levels of RAD51, which might be a potential epigenetic mechanism for high-level PM2.5 induced down-regulated expression of RAD51 and DSBs. Besides, 29 overlapped alterations in metabolic pathways were identified by metabolomic and miRNA sequencing, including purine metabolism and pyrimidine metabolism after LLPO exposure. Differential miRNAs expression in lung tissue were associated with apoptosis, DNA damage and damage repair. We concluded that under different air pollution patterns, DNA damage biomarkers and activated targets of DNA damage repair network were both different. The genetic damage effects caused by high-level short-term PM2.5 can be alleviated by natural repair. We provided possible mechanisms by multi-omics which could explain the increased carcinogenic risk caused by air pollution.
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Affiliation(s)
- Jiayu Xu
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China
| | - Qiaojian Zhang
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China
| | - Zekang Su
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China
| | - Yu Liu
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China
| | - Tenglong Yan
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China
| | - Yali Zhang
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China
| | - Tiancheng Wang
- Department of Clinical Laboratory, Third Hospital of Peking University, Beijing 100083, China
| | - Xuetao Wei
- Department of Toxicology, School of Public Health, Peking University, Beijing 100083, China
| | - Zhangjian Chen
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China
| | - Guiping Hu
- School of Medical Science and Engineering, Beihang University, Beijing 100191, China
| | - Tian Chen
- School of Public Health and Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Guang Jia
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China.
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Paccosi E, Balajee AS, Proietti-De-Santis L. A matter of delicate balance: Loss and gain of Cockayne syndrome proteins in premature aging and cancer. FRONTIERS IN AGING 2022; 3:960662. [PMID: 35935726 PMCID: PMC9351357 DOI: 10.3389/fragi.2022.960662] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/04/2022] [Indexed: 12/26/2022]
Abstract
DNA repair genes are critical for preserving genomic stability and it is well established that mutations in DNA repair genes give rise to progeroid diseases due to perturbations in different DNA metabolic activities. Cockayne Syndrome (CS) is an autosomal recessive inheritance caused by inactivating mutations in CSA and CSB genes. This review will primarily focus on the two Cockayne Syndrome proteins, CSA and CSB, primarily known to be involved in Transcription Coupled Repair (TCR). Curiously, dysregulated expression of CS proteins has been shown to exhibit differential health outcomes: lack of CS proteins due to gene mutations invariably leads to complex premature aging phenotypes, while excess of CS proteins is associated with carcinogenesis. Thus it appears that CS genes act as a double-edged sword whose loss or gain of expression leads to premature aging and cancer. Future mechanistic studies on cell and animal models of CS can lead to potential biological targets for interventions in both aging and cancer development processes. Some of these exciting possibilities will be discussed in this review in light of the current literature.
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Affiliation(s)
- Elena Paccosi
- Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, Viterbo, Italy
- *Correspondence: Elena Paccosi, ; Adayabalam S. Balajee, ; Luca Proietti-De-Santis,
| | - Adayabalam S. Balajee
- Cytogenetic Biodosimetry Laboratory, Radiation Emergency Assistance Center/Training Site, Oak Ridge Institute of Science and Education, Oak Ridge Associated Universities, Oak Ridge, TN, United States
- *Correspondence: Elena Paccosi, ; Adayabalam S. Balajee, ; Luca Proietti-De-Santis,
| | - Luca Proietti-De-Santis
- Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, Viterbo, Italy
- *Correspondence: Elena Paccosi, ; Adayabalam S. Balajee, ; Luca Proietti-De-Santis,
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8
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A Dietary Antioxidant Formulation Ameliorates DNA Damage Caused by γ-Irradiation in Normal Human Bronchial Epithelial Cells In Vitro. Antioxidants (Basel) 2022; 11:antiox11071407. [PMID: 35883898 PMCID: PMC9311589 DOI: 10.3390/antiox11071407] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/12/2022] [Accepted: 07/18/2022] [Indexed: 12/10/2022] Open
Abstract
Antioxidants can be used as radioprotectants to reduce DNA damage due to exposure to radiation that could result in malignancies, including lung cancer. Mortality rates are consistently higher in lung cancer, which is usually diagnosed at later stages of cancer development and progression. In this preliminary study, we examined the potential of an antioxidant formulation (AOX2) to reduce DNA damage using a cell model of human normal bronchial epithelial cells (BEAS-2B). Cells were exposed to γ-irradiation or smoke-related hydrocarbon 4[(acetoxymethyl)nitrosamino]-1 (3-pyridyl) 1-butanone (NNKOAc) to induce DNA damage. We monitored intracellular reactive oxygen species (ROS) levels and evidence of genotoxic damage including DNA fragmentation ELISA, γ-H2AX immunofluorescence, and comet assays. Pre-incubation of the cells with AOX2 before exposure to γ-irradiation and NNKOAc significantly reduced DNA damage. The dietary antioxidant preparation AOX2 significantly reduced the induction of the tumor suppressor protein p53 and DNA damage-associated γ-H2AX phosphorylation by radiation and the NNKOAc treatment. Thus, AOX2 has the potential to act as a chemoprotectant by lowering ROS levels and DNA damage caused by exposure to radiation or chemical carcinogens.
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Zhao Q, Chen S, Wang G, Du Y, Zhang Z, Yu G, Ren C, Zhang Y, Du J. Exogenous melatonin enhances soybean (Glycine max (L.) Merr.) seedling tolerance to saline-alkali stress by regulating antioxidant response and DNA damage repair. PHYSIOLOGIA PLANTARUM 2022; 174:e13731. [PMID: 35717632 DOI: 10.1111/ppl.13731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/13/2022] [Accepted: 06/06/2022] [Indexed: 06/15/2023]
Abstract
Saline-alkali (SA) stress induces excessive reactive oxygen species (ROS) accumulation in plant cells, resulting in oxidative damages of membranes, lipids, proteins, and nucleic acids. Melatonin has antioxidant protection effects in living organisms and thus has received a lot of attention. This study aimed to investigate the effect and regulating mechanism of melatonin treatment on soybean tolerance to SA stress. In this study, cultivars Heihe 49 (HH49, SA-tolerant) and Henong 95 (HN95, SA-sensitive) were pot-cultured in SA soil, then treated with MT (0-300 μM) at V1 stage. SA stress induced ROS accumulation and DNA damage in the seedling roots of both cultivars, causing G1/S arrest in HN95 and G2/M arrest in HH49. Melatonin treatment enhanced the activity of antioxidant enzymes in soybean seedling roots and reduced ROS accumulation. Additionally, melatonin treatment upregulated DNA damage repair genes, thus enhancing the reduction of DNA oxidative damage under SA stress. The effects of melatonin treatment were manifested as decreased RAPD polymorphism, 8-hydroxy-2'-deoxyguanine (8-OH-dG) level, and relative density of apurinic sites (AP-sites). Meanwhile, melatonin treatment partially alleviated the SA-induced G1/S arrest in HN95 and G2/M arrest in HH49, thus enhancing soybean seedling tolerance to SA stress.
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Affiliation(s)
- Qiang Zhao
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Suyu Chen
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Guangda Wang
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Yanli Du
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Zhaoning Zhang
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Gaobo Yu
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Chunyuan Ren
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Yuxian Zhang
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Jidao Du
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
- Research Center of Saline and Alkali Land Improvement Engineering Technology in Heilongjiang Province, Daqing, People's Republic of China
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10
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Feng YQ, Zhao AH, Wang JJ, Tian Y, Yan ZH, Dri M, Shen W, De Felici M, Li L. Oxidative stress as a plausible mechanism for zearalenone to induce genome toxicity. Gene 2022; 829:146511. [PMID: 35447234 DOI: 10.1016/j.gene.2022.146511] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 02/27/2022] [Accepted: 04/14/2022] [Indexed: 02/07/2023]
Abstract
Zearalenone (ZEN), a common non-steroidal estrogenic mycotoxin of the Fusarium genus, is one of the most frequent and powerful contaminant of grains and cereal products representing a serious threat for people and livestock health. In fact, ZEN causes cytotoxicity and genotoxicity in a variety of cell types at least in part through binding to estrogen receptors (ERs). The main pathways through which ZEN induces such effects remain, however, elusive. In particular, how the mycotoxin causes DNA damage, dysregulates DNA repair mechanisms, changes epigenome of targeted cells and, not least, affects chromatin conformation and non-coding RNA (ncRNA), is unclear. In the present paper, following extensive review of the literature about such ZEN effects and our own experience in studying the effects of this compound on reproductive processes, we propose that increased production of reactive oxygen species (ROS) and consequently oxidative stress (OS) are central in ZEN genotoxicity. Besides to shed light on the action mechanisms of the mycotoxin, this notion might help to develop effective strategies to counteract its deleterious biological effects.
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Affiliation(s)
- Yan-Qin Feng
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China
| | - Ai-Hong Zhao
- Qingdao Academy of Agricultural Sciences, Qingdao 266100, China
| | - Jun-Jie Wang
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China
| | - Yu Tian
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China
| | - Zi-Hui Yan
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China
| | - Maria Dri
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome 00133, Italy
| | - Wei Shen
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China
| | - Massimo De Felici
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome 00133, Italy.
| | - Lan Li
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China.
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11
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Carvalho G, Repolês BM, Mendes I, Wanrooij PH. Mitochondrial DNA Instability in Mammalian Cells. Antioxid Redox Signal 2022; 36:885-905. [PMID: 34015960 PMCID: PMC9127837 DOI: 10.1089/ars.2021.0091] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 02/06/2023]
Abstract
Significance: The small, multicopy mitochondrial genome (mitochondrial DNA [mtDNA]) is essential for efficient energy production, as alterations in its coding information or a decrease in its copy number disrupt mitochondrial ATP synthesis. However, the mitochondrial replication machinery encounters numerous challenges that may limit its ability to duplicate this important genome and that jeopardize mtDNA stability, including various lesions in the DNA template, topological stress, and an insufficient nucleotide supply. Recent Advances: An ever-growing array of DNA repair or maintenance factors are being reported to localize to the mitochondria. We review current knowledge regarding the mitochondrial factors that may contribute to the tolerance or repair of various types of changes in the mitochondrial genome, such as base damage, incorporated ribonucleotides, and strand breaks. We also discuss the newly discovered link between mtDNA instability and activation of the innate immune response. Critical Issues: By which mechanisms do mitochondria respond to challenges that threaten mtDNA maintenance? What types of mtDNA damage are repaired, and when are the affected molecules degraded instead? And, finally, which forms of mtDNA instability trigger an immune response, and how? Future Directions: Further work is required to understand the contribution of the DNA repair and damage-tolerance factors present in the mitochondrial compartment, as well as the balance between mtDNA repair and degradation. Finally, efforts to understand the events underlying mtDNA release into the cytosol are warranted. Pursuing these and many related avenues can improve our understanding of what goes wrong in mitochondrial disease. Antioxid. Redox Signal. 36, 885-905.
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Affiliation(s)
- Gustavo Carvalho
- Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
| | - Bruno Marçal Repolês
- Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
| | - Isabela Mendes
- Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
| | - Paulina H. Wanrooij
- Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
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12
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Cho E, Allemang A, Audebert M, Chauhan V, Dertinger S, Hendriks G, Luijten M, Marchetti F, Minocherhomji S, Pfuhler S, Roberts DJ, Trenz K, Yauk CL. AOP report: Development of an adverse outcome pathway for oxidative DNA damage leading to mutations and chromosomal aberrations. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2022; 63:118-134. [PMID: 35315142 PMCID: PMC9322445 DOI: 10.1002/em.22479] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 03/18/2022] [Indexed: 05/22/2023]
Abstract
The Genetic Toxicology Technical Committee (GTTC) of the Health and Environmental Sciences Institute (HESI) is developing adverse outcome pathways (AOPs) that describe modes of action leading to potentially heritable genomic damage. The goal was to enhance the use of mechanistic information in genotoxicity assessment by building empirical support for the relationships between relevant molecular initiating events (MIEs) and regulatory endpoints in genetic toxicology. Herein, we present an AOP network that links oxidative DNA damage to two adverse outcomes (AOs): mutations and chromosomal aberrations. We collected empirical evidence from the literature to evaluate the key event relationships between the MIE and the AOs, and assessed the weight of evidence using the modified Bradford-Hill criteria for causality. Oxidative DNA damage is constantly induced and repaired in cells given the ubiquitous presence of reactive oxygen species and free radicals. However, xenobiotic exposures may increase damage above baseline levels through a variety of mechanisms and overwhelm DNA repair and endogenous antioxidant capacity. Unrepaired oxidative DNA base damage can lead to base substitutions during replication and, along with repair intermediates, can also cause DNA strand breaks that can lead to mutations and chromosomal aberrations if not repaired adequately. This AOP network identifies knowledge gaps that could be filled by targeted studies designed to better define the quantitative relationships between key events, which could be leveraged for quantitative chemical safety assessment. We anticipate that this AOP network will provide the building blocks for additional genotoxicity-associated AOPs and aid in designing novel integrated testing approaches for genotoxicity.
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Affiliation(s)
- Eunnara Cho
- Environmental Health Science and Research BureauHealth CanadaOttawaOntarioCanada
- Department of BiologyCarleton UniversityOttawaOntarioCanada
| | | | | | - Vinita Chauhan
- Consumer and Clinical Radiation Protection BureauHealth CanadaOttawaOntarioCanada
| | | | | | - Mirjam Luijten
- Centre for Health ProtectionNational Institute for Public Health and the Environment (RIVM)BilthovenThe Netherlands
| | - Francesco Marchetti
- Environmental Health Science and Research BureauHealth CanadaOttawaOntarioCanada
- Department of BiologyCarleton UniversityOttawaOntarioCanada
| | - Sheroy Minocherhomji
- Amgen Research, Translational Safety and Bioanalytical SciencesAmgen Inc.Thousand OaksCaliforniaUSA
| | | | | | | | - Carole L. Yauk
- Environmental Health Science and Research BureauHealth CanadaOttawaOntarioCanada
- Department of BiologyCarleton UniversityOttawaOntarioCanada
- Department of BiologyUniversity of OttawaOttawaOntarioCanada
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13
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Tortora K, Margheri F, Luceri C, Mocali A, Ristori S, Magnelli L, Caderni G, Giovannelli L. Colon fibroblasts from Pirc rats (F344/NTac-Apc am1137 ) exhibit a proliferative and inflammatory phenotype that could support early stages of colon carcinogenesis. Int J Cancer 2022; 150:362-373. [PMID: 34486752 PMCID: PMC9291568 DOI: 10.1002/ijc.33796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 08/03/2021] [Accepted: 08/16/2021] [Indexed: 12/28/2022]
Abstract
The role of fibroblast APC mutation in carcinogenesis is not clear. Apc+/− colon fibroblasts have been previously characterized: however, little is known about their behavior at very early‐stage of colon carcinogenesis. We cultured colon mucosa fibroblasts (PCF, Apc+/−) of Pirc rats (F344/NTac‐Apcam1137) at an early stage of tumorigenesis, in absence of preneoplastic lesions, and of age‐matched wt (WCF): DNA damage levels, inflammatory phenotype and the expression of known markers of CAFs were analyzed. The latter were also assessed by microarray analysis on colon normal mucosa of Pirc and wt animals. PCF exhibited higher proliferative rates (P < .001) and delayed replicative senescence onset (P < .05) compared to WCF, along with a lower level of oxidative DNA damage (P < .05). Furthermore, a constitutively higher expression of COX‐2 and sensitivity to inflammatory stimuli was found in PCF compared to WCF (P < .05), accompanied by higher invasive capability (P < .05) and presence of cytoplasmic chromatin foci (cytoplasmic chromatin foci, P < .05). However, they neither expressed CAFs markers (α‐SMA, IL‐6) nor responded to CAFs activating stimuli (TGF‐β). Accordingly, CAFs markers and activating stimuli resulted down‐regulated in Pirc normal mucosa compared to wt, whereas DNA damage response and tolerance pathways were overexpressed. These data show for the first time that a proliferative and inflammatory phenotype characterizes Apc+/− colon fibroblasts since very early stages of colon tumorigenesis, and indicate a role of Apc mutation in driving fibroblast phenotypic alterations that could support the establishment of a protumorigenic environment. Early pharmacological targeting of these dysfunctions might impact on tumor prevention in FAP patients.
What's new?
Heterozygous mutations in APC represent the earliest event in sporadic colorectal carcinogenesis onset and cause familial adenomatous polyposis syndrome. However, the role of APC‐mutated fibroblasts remains unclear. Here, Apc+/‐ fibroblasts isolated from apparently‐normal colon tissue of Pirc rats showed proliferative, inflammatory features and resistance to oxidative DNA damage, although they did not show cancer‐associated fibroblast features. These data suggest that, at the very early stages of colon tumourigenesis, Apc‐mutated colon fibroblasts favour the establishment of a pro‐tumourigenic environment for pre‐neoplastic lesion development. Early pharmacological targeting of these dysfunctions might be valuable for tumour prevention in familial adenomatous polyposis patients.
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Affiliation(s)
- Katia Tortora
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Francesca Margheri
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Florence, Italy
| | - Cristina Luceri
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Alessandra Mocali
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Florence, Italy
| | - Sara Ristori
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Lucia Magnelli
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Florence, Italy
| | - Giovanna Caderni
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Lisa Giovannelli
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
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14
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Chmielowska-Bąk J, Izbiańska-Jankowska K, Deckert J. Estimation of the Level of Abasic Sites in Plant mRNA Using Aldehyde Reactive Probe. Methods Mol Biol 2022; 2526:125-134. [PMID: 35657516 DOI: 10.1007/978-1-0716-2469-2_9] [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: 06/15/2023]
Abstract
Oxidation of RNA is associated with the development of numerous disorders including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), cancer, and diabetes. Additionally, a correlation has been found between increase in RNA oxidation and the process of aging. In plants, elevated level of oxidatively modified transcripts has been detected during alleviation of seeds dormancy and stress response. Increasing interest on the topic of RNA oxidative modifications requires elaboration of new laboratory techniques. So far, the most common method used for the assessment of RNA oxidation is quantification of 8-hydroxyguanine (8-OHG). However, reactive oxygen species (ROS) induce also numerous other changes in nucleic acids, including formation of abasic sites (AP-sites). Recently, the level of AP-sites in RNA has been measured with the use Aldehyde Reactive Probe (ARP). In the present chapter, we describe application of this technique for the evaluation of the level of AP-sites in plant transcripts.
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Affiliation(s)
- Jagna Chmielowska-Bąk
- Department of Plant Ecophysiology, Institute of Experimental Biology, Faculty of Biology, School of Natural Sciences, Adam Mickiewicz University, Poznan, Poland.
| | - Karolina Izbiańska-Jankowska
- Department of Plant Ecophysiology, Institute of Experimental Biology, Faculty of Biology, School of Natural Sciences, Adam Mickiewicz University, Poznan, Poland
| | - Joanna Deckert
- Department of Plant Ecophysiology, Institute of Experimental Biology, Faculty of Biology, School of Natural Sciences, Adam Mickiewicz University, Poznan, Poland
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15
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Impact of G-Quadruplexes and Chronic Inflammation on Genome Instability: Additive Effects during Carcinogenesis. Genes (Basel) 2021; 12:genes12111779. [PMID: 34828385 PMCID: PMC8619830 DOI: 10.3390/genes12111779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/03/2021] [Accepted: 11/04/2021] [Indexed: 02/07/2023] Open
Abstract
Genome instability is an enabling characteristic of cancer, essential for cancer cell evolution. Hotspots of genome instability, from small-scale point mutations to large-scale structural variants, are associated with sequences that potentially form non-B DNA structures. G-quadruplex (G4) forming motifs are enriched at structural variant endpoints in cancer genomes. Chronic inflammation is a physiological state underlying cancer development, and oxidative DNA damage is commonly invoked to explain how inflammation promotes genome instability. We summarize where G4s and oxidative stress overlap, with a focus on DNA replication. Guanine has low ionization potential, making G4s vulnerable to oxidative damage. Impacts to G4 structure are dependent upon lesion type, location, and G4 conformation. Occasionally, G4s pose a challenge to replicative DNA polymerases, requiring specialized DNA polymerases to maintain genome stability. Therefore, chronic inflammation creates a dual challenge for DNA polymerases to maintain genome stability: faithful G4 synthesis and bypassing unrepaired oxidative lesions. Inflammation is also accompanied by global transcriptome changes that may impact mutagenesis. Several studies suggest a regulatory role for G4s within cancer- and inflammatory-related gene promoters. We discuss the extent to which inflammation could influence gene regulation by G4s, thereby impacting genome instability, and highlight key areas for new investigation.
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16
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Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma. Cancers (Basel) 2021; 13:cancers13133211. [PMID: 34199066 PMCID: PMC8269013 DOI: 10.3390/cancers13133211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/14/2021] [Accepted: 06/23/2021] [Indexed: 12/20/2022] Open
Abstract
Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response.
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17
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Kajitani GS, Nascimento LLDS, Neves MRDC, Leandro GDS, Garcia CCM, Menck CFM. Transcription blockage by DNA damage in nucleotide excision repair-related neurological dysfunctions. Semin Cell Dev Biol 2021; 114:20-35. [DOI: 10.1016/j.semcdb.2020.10.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 08/18/2020] [Accepted: 10/07/2020] [Indexed: 12/20/2022]
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Willaume S, Rass E, Fontanilla-Ramirez P, Moussa A, Wanschoor P, Bertrand P. A Link between Replicative Stress, Lamin Proteins, and Inflammation. Genes (Basel) 2021; 12:genes12040552. [PMID: 33918867 PMCID: PMC8070205 DOI: 10.3390/genes12040552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/23/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022] Open
Abstract
Double-stranded breaks (DSB), the most toxic DNA lesions, are either a consequence of cellular metabolism, programmed as in during V(D)J recombination, or induced by anti-tumoral therapies or accidental genotoxic exposure. One origin of DSB sources is replicative stress, a major source of genome instability, especially when the integrity of the replication forks is not properly guaranteed. To complete stalled replication, restarting the fork requires complex molecular mechanisms, such as protection, remodeling, and processing. Recently, a link has been made between DNA damage accumulation and inflammation. Indeed, defects in DNA repair or in replication can lead to the release of DNA fragments in the cytosol. The recognition of this self-DNA by DNA sensors leads to the production of inflammatory factors. This beneficial response activating an innate immune response and destruction of cells bearing DNA damage may be considered as a novel part of DNA damage response. However, upon accumulation of DNA damage, a chronic inflammatory cellular microenvironment may lead to inflammatory pathologies, aging, and progression of tumor cells. Progress in understanding the molecular mechanisms of DNA damage repair, replication stress, and cytosolic DNA production would allow to propose new therapeutical strategies against cancer or inflammatory diseases associated with aging. In this review, we describe the mechanisms involved in DSB repair, the replicative stress management, and its consequences. We also focus on new emerging links between key components of the nuclear envelope, the lamins, and DNA repair, management of replicative stress, and inflammation.
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19
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Paccosi E, Proietti-De-Santis L. The emerging role of Cockayne group A and B proteins in ubiquitin/proteasome-directed protein degradation. Mech Ageing Dev 2021; 195:111466. [PMID: 33727156 DOI: 10.1016/j.mad.2021.111466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/16/2021] [Accepted: 03/02/2021] [Indexed: 12/18/2022]
Abstract
When mutated, csa and csb genes are responsible of the complex phenotype of the premature aging Cockayne Syndrome (CS). Our working hypothesis is to reconcile the multiple cellular and molecular phenotypes associated to CS within the unifying molecular function of CSA and CSB proteins in the cascade of events leading to ubiquitin/proteasome-directed protein degradation, which occurs in processes as DNA repair, transcription and cell division. This achievement may reasonably explain the plethora of cellular UPS-regulated functions that result impaired when either CSA or CSB are mutated and suggestively explains part of their pleiotropic effect. This review is aimed to solicit the interest of the scientific community in further investigating this aspect, since we believe that the identification of the ubiquitin-proteasome machinery as a new potential therapeutic target, able to comprehensively face the different molecular aspects of CS, whether confirmed and corroborated by in vivo studies, would open a promising avenue to design effective therapeutic intervention.
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Affiliation(s)
- Elena Paccosi
- Unit of Molecular Genetics of Aging, Department of Ecological and Biological Sciences, Università degli Studi della Tuscia, Viterbo, Italy
| | - Luca Proietti-De-Santis
- Unit of Molecular Genetics of Aging, Department of Ecological and Biological Sciences, Università degli Studi della Tuscia, Viterbo, Italy.
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20
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The Cockayne syndrome group A and B proteins are part of a ubiquitin-proteasome degradation complex regulating cell division. Proc Natl Acad Sci U S A 2020; 117:30498-30508. [PMID: 33199595 DOI: 10.1073/pnas.2006543117] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Cytokinesis is monitored by a molecular machinery that promotes the degradation of the intercellular bridge, a transient protein structure connecting the two daughter cells. Here, we found that CSA and CSB, primarily defined as DNA repair factors, are located at the midbody, a transient structure in the middle of the intercellular bridge, where they recruit CUL4 and MDM2 ubiquitin ligases and the proteasome. As a part of this molecular machinery, CSA and CSB contribute to the ubiquitination and the degradation of proteins such as PRC1, the Protein Regulator of Cytokinesis, to ensure the correct separation of the two daughter cells. Defects in CSA or CSB result in perturbation of the abscission leading to the formation of long intercellular bridges and multinucleated cells, which might explain part of the Cockayne syndrome phenotypes. Our results enlighten the role played by CSA and CSB as part of a ubiquitin/proteasome degradation process involved in transcription, DNA repair, and cell division.
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21
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Smith MT, Guyton KZ, Kleinstreuer N, Borrel A, Cardenas A, Chiu WA, Felsher DW, Gibbons CF, Goodson WH, Houck KA, Kane AB, La Merrill MA, Lebrec H, Lowe L, McHale CM, Minocherhomji S, Rieswijk L, Sandy MS, Sone H, Wang A, Zhang L, Zeise L, Fielden M. The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them. Cancer Epidemiol Biomarkers Prev 2020; 29:1887-1903. [PMID: 32152214 PMCID: PMC7483401 DOI: 10.1158/1055-9965.epi-19-1346] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/15/2020] [Accepted: 03/04/2020] [Indexed: 12/21/2022] Open
Abstract
The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."
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Affiliation(s)
- Martyn T Smith
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California.
| | - Kathryn Z Guyton
- Monographs Programme, International Agency for Research on Cancer, Lyon, France
| | - Nicole Kleinstreuer
- Division of Intramural Research, Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina
- National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Alexandre Borrel
- Division of Intramural Research, Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina
| | - Andres Cardenas
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California
| | - Weihsueh A Chiu
- Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas
| | - Dean W Felsher
- Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California
| | - Catherine F Gibbons
- Office of Research and Development, US Environmental Protection Agency, Washington, D.C
| | - William H Goodson
- California Pacific Medical Center Research Institute, San Francisco, California
| | - Keith A Houck
- Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina
| | - Agnes B Kane
- Department of Pathology and Laboratory Medicine, Alpert Medical School, Brown University, Providence, Rhode Island
| | - Michele A La Merrill
- Department of Environmental Toxicology, University of California, Davis, California
| | - Herve Lebrec
- Comparative Biology & Safety Sciences, Amgen Research, Amgen Inc., Thousand Oaks, California
| | - Leroy Lowe
- Getting to Know Cancer, Truro, Nova Scotia, Canada
| | - Cliona M McHale
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California
| | - Sheroy Minocherhomji
- Comparative Biology & Safety Sciences, Amgen Research, Amgen Inc., Thousand Oaks, California
| | - Linda Rieswijk
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California
- Institute of Data Science, Maastricht University, Maastricht, the Netherlands
| | - Martha S Sandy
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California
| | - Hideko Sone
- Yokohama University of Pharmacy and National Institute for Environmental Studies, Tsukuba Ibaraki, Japan
| | - Amy Wang
- Office of the Report on Carcinogens, Division of National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California
| | - Lauren Zeise
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California
| | - Mark Fielden
- Expansion Therapeutics Inc, San Diego, California
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22
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Han B, Pei Z, Shi L, Wang Q, Li C, Zhang B, Su X, Zhang N, Zhou L, Zhao B, Niu Y, Zhang R. TiO 2 Nanoparticles Caused DNA Damage in Lung and Extra-Pulmonary Organs Through ROS-Activated FOXO3a Signaling Pathway After Intratracheal Administration in Rats. Int J Nanomedicine 2020; 15:6279-6294. [PMID: 32904047 PMCID: PMC7449758 DOI: 10.2147/ijn.s254969] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/17/2020] [Indexed: 01/01/2023] Open
Abstract
Introduction Because of the increased production and application of manufactured Nano-TiO2 in the past several years, it is important to investigate its potential hazards. TiO2 is classified by IARC as a possible human carcinogen; however, the potential mechanism of carcinogenesis has not been studied clearly. The present study aimed to investigate the mechanism of DNA damage in rat lung and extra-pulmonary organs caused by TiO2nanoparticles. Methods In the present study, SD rats were exposed to Nano-TiO2 by intratracheal injection at a dose of 0, 0.2, or 1 g/kg body weight. The titanium levels in tissues were detected by ICP-MS. Western blot was used to detect the protein expression levels. The DNA damage and oxidative stress were detected by comet assay and ROS, MDA, SOD, and GSH-Px levels, respectively. Results The titanium levels of the 1 g/kg group on day-3 and day-7 were significantly increased in liver and kidney as well as significantly decreased in lung compared to day-1. ROS and MDA levels were statistically increased, whereas SOD and GSH-Px levels were statistically decreased in tissues of rats in dose-dependent manners after Nano-TiO2 treatment. PI3K, p-AKT/AKT, and p-FOXO3a/FOXO3a in lung, liver, and kidney activated in dose-dependent manners. The levels of DNA damage in liver, kidney, and lung in each Nano-TiO2 treatment group were significantly increased and could not recover within 7 days. GADD45α, ChK2, and XRCC1 in liver, kidney, and lung of rats exposed to Nano-TiO2 statistically increased, which triggered DNA repair. Conclusion This work demonstrated that Ti could deposit in lung and enter extra-pulmonary organs of rats and cause oxidative stress, then trigger DNA damage through activating the PI3K-AKT-FOXO3a pathway and then promoting GADD45α, ChK2, and XRCC1 to process the DNA repair.
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Affiliation(s)
- Bin Han
- Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Zijie Pei
- Department of Pathology, Medical School, China Three Gorge University, Yichang 443002, People's Republic of China
| | - Lei Shi
- Occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Qian Wang
- Experimental Center, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Chen Li
- Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Boyuan Zhang
- Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Xuan Su
- Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Ning Zhang
- Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Lixiao Zhou
- Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Bo Zhao
- Department of Laboratory Diagnosis, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Yujie Niu
- Occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China.,Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
| | - Rong Zhang
- Department of Toxicology, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China.,Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China
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Ligand-induced gene activation is associated with oxidative genome damage whose repair is required for transcription. Proc Natl Acad Sci U S A 2020; 117:22183-22192. [PMID: 32826329 PMCID: PMC7486736 DOI: 10.1073/pnas.1919445117] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The endogenous genome damage induced by mitochondrial/cytosolic reactive oxygen species (ROS) is well recognized. However, similar damage induced by nuclear ROS generated via histone/cytosine-phosphate-guanine (CpG) demethylation during transcription has not been scrupulously investigated. This report documents the formation of genomic oxidized bases and single-strand breaks during ligand-induced gene activation via histone/CpG demethylation. That repair of these damages occurs preferentially in promoters and is essential for transcriptional activation underscore the essentiality of promoter-specific repair for transcription. In contrast, heat shock (HS) induction generates double-strand breaks, the repair of which is essential for the activation of HS-responsive genes. This study thus implies gross underestimation of endogenous oxidative genome damage and highlights the intrinsic diversity of damage and distinct repair processes associated with transcription. Among several reversible epigenetic changes occurring during transcriptional activation, only demethylation of histones and cytosine-phosphate-guanines (CpGs) in gene promoters and other regulatory regions by specific demethylase(s) generates reactive oxygen species (ROS), which oxidize DNA and other cellular components. Here, we show induction of oxidized bases and single-strand breaks (SSBs), but not direct double-strand breaks (DSBs), in the genome during gene activation by ligands of the nuclear receptor superfamily. We observed that these damages were preferentially repaired in promoters via the base excision repair (BER)/single-strand break repair (SSBR) pathway. Interestingly, BER/SSBR inhibition suppressed gene activation. Constitutive association of demethylases with BER/SSBR proteins in multiprotein complexes underscores the coordination of histone/DNA demethylation and genome repair during gene activation. However, ligand-independent transcriptional activation occurring during heat shock (HS) induction is associated with the generation of DSBs, the repair of which is likewise essential for the activation of HS-responsive genes. These observations suggest that the repair of distinct damages induced during diverse transcriptional activation is a universal prerequisite for transcription initiation. Because of limited investigation of demethylation-induced genome damage during transcription, this study suggests that the extent of oxidative genome damage resulting from various cellular processes is substantially underestimated.
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24
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Distinct roles of XRCC1 in genome integrity in Xenopus egg extracts. Biochem J 2020; 476:3791-3804. [PMID: 31808793 DOI: 10.1042/bcj20190798] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/04/2019] [Accepted: 12/06/2019] [Indexed: 02/06/2023]
Abstract
Oxidative DNA damage represents one of the most abundant DNA lesions. It remains unclear how DNA repair and DNA damage response (DDR) pathways are co-ordinated and regulated following oxidative stress. While XRCC1 has been implicated in DNA repair, it remains unknown how exactly oxidative DNA damage is repaired and sensed by XRCC1. In this communication, we have demonstrated evidence that XRCC1 is dispensable for ATR-Chk1 DDR pathway following oxidative stress in Xenopus egg extracts. Whereas APE2 is essential for SSB repair, XRCC1 is not required for the repair of defined SSB and gapped plasmids with a 5'-OH or 5'-P terminus, suggesting that XRCC1 and APE2 may contribute to SSB repair via different mechanisms. Neither Polymerase beta nor Polymerase alpha is important for the repair of defined SSB structure. Nonetheless, XRCC1 is important for the repair of DNA damage following oxidative stress. Our observations suggest distinct roles of XRCC1 for genome integrity in oxidative stress in Xenopus egg extracts.
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25
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Daley JM, Tomimatsu N, Hooks G, Wang W, Miller AS, Xue X, Nguyen KA, Kaur H, Williamson E, Mukherjee B, Hromas R, Burma S, Sung P. Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions. Nat Commun 2020; 11:3088. [PMID: 32555206 PMCID: PMC7303207 DOI: 10.1038/s41467-020-16903-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 05/29/2020] [Indexed: 12/19/2022] Open
Abstract
DNA double-strand break repair by homologous recombination begins with nucleolytic resection of the 5’ DNA strand at the break ends. Long-range resection is catalyzed by EXO1 and BLM-DNA2, which likely have to navigate through ribonucleotides and damaged bases. Here, we show that a short stretch of ribonucleotides at the 5’ terminus stimulates resection by EXO1. Ribonucleotides within a 5’ flap are resistant to cleavage by DNA2, and extended RNA:DNA hybrids inhibit both strand separation by BLM and resection by EXO1. Moreover, 8-oxo-guanine impedes EXO1 but enhances resection by BLM-DNA2, and an apurinic/apyrimidinic site stimulates resection by BLM-DNA2 and DNA strand unwinding by BLM. Accordingly, depletion of OGG1 or APE1 leads to greater dependence of DNA resection on DNA2. Importantly, RNase H2A deficiency impairs resection overall, which we attribute to the accumulation of long RNA:DNA hybrids at DNA ends. Our results help explain why eukaryotic cells possess multiple resection nucleases. DNA double-strand break repair by homologous recombination initiates with nucleolytic resection of the 5’ DNA strand at the break ends. Here, the authors reveal that the lesion context influences the action and efficiency of the long range resection factors EXO1 and BLM-DNA2.
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Affiliation(s)
- James M Daley
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06510, USA. .,Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
| | - Nozomi Tomimatsu
- Department of Neurosurgery, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Grace Hooks
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06510, USA.,Department of Biochemistry, Duke University, Durham, NC, 27710, USA
| | - Weibin Wang
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06510, USA.,Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Adam S Miller
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06510, USA.,Regeneron, Rensselaer, NY, 12144, USA
| | - Xiaoyu Xue
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06510, USA.,Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, USA
| | - Kevin A Nguyen
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06510, USA.,David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Hardeep Kaur
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Elizabeth Williamson
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Bipasha Mukherjee
- Department of Neurosurgery, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Robert Hromas
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Sandeep Burma
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229, USA. .,Department of Neurosurgery, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
| | - Patrick Sung
- Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06510, USA. .,Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
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26
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Liptay M, Barbosa JS, Rottenberg S. Replication Fork Remodeling and Therapy Escape in DNA Damage Response-Deficient Cancers. Front Oncol 2020; 10:670. [PMID: 32432041 PMCID: PMC7214843 DOI: 10.3389/fonc.2020.00670] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/09/2020] [Indexed: 12/27/2022] Open
Abstract
Most cancers have lost a critical DNA damage response (DDR) pathway during tumor evolution. These alterations provide a useful explanation for the initial sensitivity of tumors to DNA-targeting chemotherapy. A striking example is dysfunctional homology-directed repair (HDR), e.g., due to inactivating mutations in BRCA1 and BRCA2 genes. Extensive efforts are being made to develop novel targeted therapies exploiting such an HDR defect. Inhibitors of poly(ADP-ribose) polymerase (PARP) are an instructive example of this approach. Despite the success of PARP inhibitors, the presence of primary or acquired therapy resistance remains a major challenge in clinical oncology. To move the field of precision medicine forward, we need to understand the precise mechanisms causing therapy resistance. Using preclinical models, various mechanisms underlying chemotherapy resistance have been identified. Restoration of HDR seems to be a prevalent mechanism but this does not explain resistance in all cases. Interestingly, some factors involved in DNA damage response (DDR) have independent functions in replication fork (RF) biology and their loss causes RF instability and therapy sensitivity. However, in BRCA-deficient tumors, loss of these factors leads to restored stability of RFs and acquired drug resistance. In this review we discuss the recent advances in the field of RF biology and its potential implications for chemotherapy response in DDR-defective cancers. Additionally, we review the role of DNA damage tolerance (DDT) pathways in maintenance of genome integrity and their alterations in cancer. Furthermore, we refer to novel tools that, combined with a better understanding of drug resistance mechanisms, may constitute a great advance in personalized diagnosis and therapeutic strategies for patients with HDR-deficient tumors.
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Affiliation(s)
- Martin Liptay
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Joana S. Barbosa
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Sven Rottenberg
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Bern Center for Precision Medicine, University of Bern, Bern, Switzerland
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27
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Grøsvik K, Tesfahun AN, Muruzábal-Lecumberri I, Haugland GT, Leiros I, Ruoff P, Kvaløy JT, Knævelsrud I, Ånensen H, Alexeeva M, Sato K, Matsuda A, Alseth I, Klungland A, Bjelland S. The Escherichia coli alkA Gene Is Activated to Alleviate Mutagenesis by an Oxidized Deoxynucleoside. Front Microbiol 2020; 11:263. [PMID: 32158436 PMCID: PMC7051996 DOI: 10.3389/fmicb.2020.00263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 02/04/2020] [Indexed: 12/01/2022] Open
Abstract
The cellular methyl donor S-adenosylmethionine (SAM) and other endo/exogenous agents methylate DNA bases non-enzymatically into products interfering with replication and transcription. An important product is 3-methyladenine (m3A), which in Escherichia coli is removed by m3A-DNA glycosylase I (Tag) and II (AlkA). The tag gene is constitutively expressed, while alkA is induced by sub-lethal concentrations of methylating agents. We previously found that AlkA exhibits activity for the reactive oxygen-induced thymine (T) lesion 5-formyluracil (fU) in vitro. Here, we provide evidence for AlkA involvement in the repair of oxidized bases by showing that the adenine (A) ⋅ T → guanine (G) ⋅ cytosine (C) mutation rate increased 10-fold in E. coli wild-type and alkA– cells exposed to 0.1 mM 5-formyl-2′-deoxyuridine (fdU) compared to a wild-type specific reduction of the mutation rate at 0.2 mM fdU, which correlated with alkA gene induction. G⋅C → A⋅T alleviation occurred without alkA induction (at 0.1 mM fdU), correlating with a much higher AlkA efficiency for fU opposite to G than for that to A. The common keto form of fU is the AlkA substrate. Mispairing with G by ionized fU is favored by its exclusion from the AlkA active site.
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Affiliation(s)
- Kristin Grøsvik
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | - Almaz Nigatu Tesfahun
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | - Izaskun Muruzábal-Lecumberri
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | | | - Ingar Leiros
- The Norwegian Structural Biology Centre, Department of Chemistry, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Peter Ruoff
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | - Jan Terje Kvaløy
- Department of Mathematics and Physics, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | - Ingeborg Knævelsrud
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | - Hilde Ånensen
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | - Marina Alexeeva
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
| | - Kousuke Sato
- Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Tobetsu, Japan
| | - Akira Matsuda
- Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Ingrun Alseth
- Department of Microbiology, Oslo University Hospital, Oslo, Norway
| | - Arne Klungland
- Department of Microbiology, Oslo University Hospital, Oslo, Norway.,Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Svein Bjelland
- Department of Chemistry, Bioscience and Environmental Technology, Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway
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28
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Arena C, Vitale L, Bianchi AR, Mistretta C, Vitale E, Parisi C, Guerriero G, Magliulo V, De Maio A. The Ageing Process Affects the Antioxidant Defences and the Poly (ADPribosyl)ation Activity in Cistus Incanus L. Leaves. Antioxidants (Basel) 2019; 8:E528. [PMID: 31698730 PMCID: PMC6912739 DOI: 10.3390/antiox8110528] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/25/2019] [Accepted: 11/04/2019] [Indexed: 12/22/2022] Open
Abstract
The ageing process in living organisms is characterised by the accumulation of several deleterious changes occurring in cells and tissues. The increase of reactive oxygen species with the advancement of age is responsible for the oxidative damage to proteins, lipids and DNA, enhancing the risk of diseases. The antioxidant response and the activation of the poly(ADP-ribosyl)ation process represent the first defences activated by organisms at all life stages to counteract damage to cell structures and genomic material. The regulation of poly(ADP ribosyl)ation with age is little known in plants, especially in combination with antioxidant defences modulation. In this study, the relationships between poly (ADP-ribose) polymerase (PARP) activity and enzymatic and non-enzymatic antioxidant pool have been studied together with the photosynthetic apparatus efficiency in the Mediterranean species Cistus incanus L., examining leaves at different developmental stages: young, mature and senescent. The photosynthetic performance was evaluated by chlorophyll a fluorescence measurement, the total soluble and fat-soluble antioxidant capacity, as well as the activities of enzymes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) and glutathione-S-transferase (GST), were determined by spectrophotometer, PARP activity was assessed by radioactive labelling. The highest photochemical activity was observed in young leaves, together with the highest GST activity. With the progress of the ageing process, the non-enzymatic antioxidant pool (namely ascorbic acid, α-tocopherol) declined, reaching the lowest value in senescent leaves, whereas PARP activity rose significantly. The overall results indicate that the decline of photosynthetic apparatus efficiency during senescence is due to the reduction of specific defences against oxidative damages, which increase the damages to DNA, as demonstrated by PARP activity rise.
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Affiliation(s)
- Carmen Arena
- Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Via Cinthia, 80126 Napoli, Italy; (C.A.); (A.R.B.); (E.V.); (C.P.); (G.G.)
| | - Luca Vitale
- Istituto per i Sistemi Agricoli e Forestali del Mediterraneo (CNR-ISAFoM), Via Patacca 85, 80056 Ercolano (NA), Italy; (L.V.); (C.M.); (V.M.)
| | - Anna Rita Bianchi
- Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Via Cinthia, 80126 Napoli, Italy; (C.A.); (A.R.B.); (E.V.); (C.P.); (G.G.)
| | - Carmela Mistretta
- Istituto per i Sistemi Agricoli e Forestali del Mediterraneo (CNR-ISAFoM), Via Patacca 85, 80056 Ercolano (NA), Italy; (L.V.); (C.M.); (V.M.)
| | - Ermenegilda Vitale
- Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Via Cinthia, 80126 Napoli, Italy; (C.A.); (A.R.B.); (E.V.); (C.P.); (G.G.)
| | - Costantino Parisi
- Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Via Cinthia, 80126 Napoli, Italy; (C.A.); (A.R.B.); (E.V.); (C.P.); (G.G.)
| | - Giulia Guerriero
- Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Via Cinthia, 80126 Napoli, Italy; (C.A.); (A.R.B.); (E.V.); (C.P.); (G.G.)
| | - Vincenzo Magliulo
- Istituto per i Sistemi Agricoli e Forestali del Mediterraneo (CNR-ISAFoM), Via Patacca 85, 80056 Ercolano (NA), Italy; (L.V.); (C.M.); (V.M.)
| | - Anna De Maio
- Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Via Cinthia, 80126 Napoli, Italy; (C.A.); (A.R.B.); (E.V.); (C.P.); (G.G.)
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29
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Pintado-Berninches L, Fernandez-Varas B, Benitez-Buelga C, Manguan-Garcia C, Serrano-Benitez A, Iarriccio L, Carrillo J, Guenechea G, Egusquiaguirre SP, Pedraz JL, Hernández RM, Igartua M, Arias-Salgado EG, Cortés-Ledesma F, Sastre L, Perona R. GSE4 peptide suppresses oxidative and telomere deficiencies in ataxia telangiectasia patient cells. Cell Death Differ 2019; 26:1998-2014. [PMID: 30670828 PMCID: PMC6748109 DOI: 10.1038/s41418-018-0272-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 11/21/2018] [Accepted: 12/03/2018] [Indexed: 01/05/2023] Open
Abstract
Ataxia telangiectasia (AT) is a genetic disease caused by mutations in the ATM gene but the mechanisms underlying AT are not completely understood. Key functions of the ATM protein are to sense and regulate cellular redox status and to transduce DNA double-strand break signals to downstream effectors. ATM-deficient cells show increased ROS accumulation, activation of p38 protein kinase, and increased levels of DNA damage. GSE24.2 peptide and a short derivative GSE4 peptide corresponding to an internal domain of Dyskerin have proved to induce telomerase activity, decrease oxidative stress, and protect from DNA damage in dyskeratosis congenita (DC) cells. We have found that expression of GSE24.2 and GSE4 in human AT fibroblast is able to decrease DNA damage, detected by γ-H2A.X and 53BP1 foci. However, GSE24.2/GSE4 expression does not improve double-strand break signaling and repair caused by the lack of ATM activity. In contrast, they cause a decrease in 8-oxoguanine and OGG1-derived lesions, particularly at telomeres and mitochondrial DNA, as well as in reactive oxygen species, in parallel with increased expression of SOD1. These cells also showed lower levels of IL6 and decreased p38 phosphorylation, decreased senescence and increased ability to divide for longer times. Additionally, these cells are more resistant to treatment with H202 and the radiomimetic-drug bleomycin. Finally, we found shorter telomere length (TL) in AT cells, lower levels of TERT expression, and telomerase activity that were also partially reverted by GSE4. These observations suggest that GSE4 may be considered as a new therapy for the treatment of AT that counteracts the cellular effects of high ROS levels generated in AT cells and in addition increases telomerase activity contributing to increased cell proliferation.
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Affiliation(s)
- Laura Pintado-Berninches
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain
- Advanced Medical Projects, Madrid, Spain
| | - Beatriz Fernandez-Varas
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain
| | | | - Cristina Manguan-Garcia
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain
- CIBER de Enfermedades Raras, Madrid, Spain
| | - Almudena Serrano-Benitez
- Centro Andaluz de Biologia Molecular y Medicina regenerativa (CABIMER) - CSIC, Universidad de Sevilla, Universidad Pablo de Olavide, Sevilla, Spain
| | - Laura Iarriccio
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain
- Advanced Medical Projects, Madrid, Spain
| | - Jaime Carrillo
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain
| | - Guillermo Guenechea
- CIBER de Enfermedades Raras, Madrid, Spain
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
- Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Susana P Egusquiaguirre
- NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country, School of Pharmacy, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Jose-Luis Pedraz
- NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country, School of Pharmacy, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Rosa M Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country, School of Pharmacy, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Manoli Igartua
- NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country, School of Pharmacy, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Elena G Arias-Salgado
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain
- Advanced Medical Projects, Madrid, Spain
| | - Felipe Cortés-Ledesma
- Centro Andaluz de Biologia Molecular y Medicina regenerativa (CABIMER) - CSIC, Universidad de Sevilla, Universidad Pablo de Olavide, Sevilla, Spain
| | - Leandro Sastre
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain
- CIBER de Enfermedades Raras, Madrid, Spain
| | - Rosario Perona
- Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain.
- CIBER de Enfermedades Raras, Madrid, Spain.
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30
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Lagundžin D, Hu WF, Law HCH, Krieger KL, Qiao F, Clement EJ, Drincic AT, Nedić O, Naldrett MJ, Alvarez S, Woods NT. Delineating the role of FANCA in glucose-stimulated insulin secretion in β cells through its protein interactome. PLoS One 2019; 14:e0220568. [PMID: 31461451 PMCID: PMC6713327 DOI: 10.1371/journal.pone.0220568] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 07/18/2019] [Indexed: 12/31/2022] Open
Abstract
Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucose-stimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas β cell line EndoC-βH3. To identify potential pathways by which FANCA might regulate GSIS, we employed a proteomics approach to identify FANCA protein interactions in EndoC-βH3 differentially regulated in response to elevated glucose levels. Glucose-dependent changes in the FANCA interaction network were observed, including increased association with other FA family proteins, suggesting an activation of the DNA damage response in response to elevated glucose levels. Reactive oxygen species increase in response to glucose stimulation and are necessary for GSIS in EndoC-βH3 cells. Glucose-induced activation of the DNA damage response was also observed as an increase in the DNA damage foci marker γ-H2AX and dependent upon the presence of reactive oxygen species. These results illuminate the role of FANCA in GSIS and its protein interactions regulated by glucose stimulation that may explain the prevalence of β cell-specific endocrinopathies in FA patients.
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Affiliation(s)
- Dragana Lagundžin
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Wen-Feng Hu
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Henry C. H. Law
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Kimiko L. Krieger
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Fangfang Qiao
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Emalie J. Clement
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Andjela T. Drincic
- Department of Internal Medicine: Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Olgica Nedić
- Institute for the Application of Nuclear Energy, University of Belgrade, Banatska, Belgrade, Serbia
| | - Michael J. Naldrett
- Proteomics & Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska–Lincoln, Nebraska, United States of America
| | - Sophie Alvarez
- Proteomics & Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska–Lincoln, Nebraska, United States of America
| | - Nicholas T. Woods
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- * E-mail:
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Killelea T, Palud A, Akcha F, Lemor M, L'haridon S, Godfroy A, Henneke G. The interplay at the replisome mitigates the impact of oxidative damage on the genetic integrity of hyperthermophilic Archaea. eLife 2019; 8:45320. [PMID: 31184586 PMCID: PMC6559790 DOI: 10.7554/elife.45320] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/28/2019] [Indexed: 12/12/2022] Open
Abstract
8-oxodeoxyguanosine (8-oxodG), a major oxidised base modification, has been investigated to study its impact on DNA replication in hyperthermophilic Archaea. Here we show that 8-oxodG is formed in the genome of growing cells, with elevated levels following exposure to oxidative stress. Functional characterisation of cell-free extracts and the DNA polymerisation enzymes, PolB, PolD, and the p41/p46 complex, alone or in the presence of accessory factors (PCNA and RPA) indicates that translesion synthesis occurs under replicative conditions. One of the major polymerisation effects was stalling, but each of the individual proteins could insert and extend past 8-oxodG with differing efficiencies. The introduction of RPA and PCNA influenced PolB and PolD in similar ways, yet provided a cumulative enhancement to the polymerisation performance of p41/p46. Overall, 8-oxodG translesion synthesis was seen to be potentially mutagenic leading to errors that are reminiscent of dA:8-oxodG base pairing.
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Affiliation(s)
- Tom Killelea
- Univ Brest, Ifremer, CNRS, Laboratoire de Microbiologie des Environnements Extrêmes, Plouzané, France
| | - Adeline Palud
- Univ Brest, Ifremer, CNRS, Laboratoire de Microbiologie des Environnements Extrêmes, Plouzané, France
| | - Farida Akcha
- Laboratoire d'Ecotoxicologie, Ifremer, Nantes, France
| | - Mélanie Lemor
- Univ Brest, Ifremer, CNRS, Laboratoire de Microbiologie des Environnements Extrêmes, Plouzané, France
| | - Stephane L'haridon
- Univ Brest, Ifremer, CNRS, Laboratoire de Microbiologie des Environnements Extrêmes, Plouzané, France
| | - Anne Godfroy
- Univ Brest, Ifremer, CNRS, Laboratoire de Microbiologie des Environnements Extrêmes, Plouzané, France
| | - Ghislaine Henneke
- Univ Brest, Ifremer, CNRS, Laboratoire de Microbiologie des Environnements Extrêmes, Plouzané, France
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32
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Ameziane El Hassani R, Buffet C, Leboulleux S, Dupuy C. Oxidative stress in thyroid carcinomas: biological and clinical significance. Endocr Relat Cancer 2019; 26:R131-R143. [PMID: 30615595 DOI: 10.1530/erc-18-0476] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 01/07/2019] [Indexed: 12/16/2022]
Abstract
At physiological concentrations, reactive oxygen species (ROS), including superoxide anions and H2O2, are considered as second messengers that play key roles in cellular functions, such as proliferation, gene expression, host defence and hormone synthesis. However, when they are at supraphysiological levels, ROS are considered potent DNA-damaging agents. Their increase induces oxidative stress, which can initiate and maintain genomic instability. The thyroid gland represents a good model for studying the impact of oxidative stress on genomic instability. Indeed, one particularity of this organ is that follicular thyroid cells synthesise thyroid hormones through a complex mechanism that requires H2O2. Because of their detection in thyroid adenomas and in early cell transformation, both oxidative stress and DNA damage are believed to be neoplasia-preceding events in thyroid cells. Oxidative DNA damage is, in addition, detected in the advanced stages of thyroid cancer, suggesting that oxidative lesions of DNA also contribute to the maintenance of genomic instability during the subsequent phases of tumourigenesis. Finally, ionizing radiation and the mutation of oncogenes, such as RAS and BRAF, play a key role in thyroid carcinogenesis through separate and unique mechanisms: they upregulate the expression of two distinct 'professional' ROS-generating systems, the NADPH oxidases DUOX1 and NOX4, which cause DNA damage that may promote chromosomal instability, tumourigenesis and dedifferentiation.
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Affiliation(s)
- Rabii Ameziane El Hassani
- Laboratory of Biology of Human Pathologies 'BioPatH', Faculty of Sciences, Mohammed V University of Rabat, Rabat, Morocco
| | - Camille Buffet
- UMR 8200 CNRS, Gustave Roussy and Paris Sud University, Villejuif, France
| | - Sophie Leboulleux
- Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Paris Sud University, Villejuif, France
| | - Corinne Dupuy
- UMR 8200 CNRS, Gustave Roussy and Paris Sud University, Villejuif, France
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33
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Melnick RL. Commentary on the utility of the National Toxicology Program study on cell phone radiofrequency radiation data for assessing human health risks despite unfounded criticisms aimed at minimizing the findings of adverse health effects. ENVIRONMENTAL RESEARCH 2019; 168:1-6. [PMID: 30243215 DOI: 10.1016/j.envres.2018.09.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 03/20/2018] [Accepted: 09/07/2018] [Indexed: 05/14/2023]
Abstract
The National Toxicology Program (NTP) conducted two-year studies of cell phone radiation in rats and mice exposed to CDMA- or GSM-modulated radiofrequency radiation (RFR) at exposure intensities in the brain of rats that were similar to or only slightly higher than potential, localized human exposures from cell phones held next to the head. This study was designed to test the (null) hypothesis that cell phone radiation at non-thermal exposure intensities could not cause adverse health effects, and to provide dose-response data for any detected toxic or carcinogenic effects. Partial findings released from that study showed significantly increased incidences and/or trends for gliomas and glial cell hyperplasias in the brain and schwannomas and Schwann cell hyperplasias in the heart of exposed male rats. These results, as well as the findings of significantly increased DNA damage (strand breaks) in the brains of exposed rats and mice, reduced pup birth weights when pregnant dams were exposed to GSM- or CDMA-modulated RFR, and the induction of cardiomyopathy of the right ventricle in male and female rats clearly demonstrate that the null hypothesis has been disproved. The NTP findings are most important because the International Agency for Research on Cancer (IARC) classified RFR as a "possible human carcinogen" based largely on increased risks of gliomas and acoustic neuromas (which are Schwann cell tumors on the acoustic nerve) among long term users of cell phones. The concordance between rats and humans in cell type affected by RFR strengthens the animal-to-human association. This commentary addresses several unfounded criticisms about the design and results of the NTP study that have been promoted to minimize the utility of the experimental data on RFR for assessing human health risks. In contrast to those criticisms, an expert peer-review panel recently concluded that the NTP studies were well designed, and that the results demonstrated that both GSM- and CDMA-modulated RFR were carcinogenic to the heart (schwannomas) and brain (gliomas) of male rats.
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Affiliation(s)
- Ronald L Melnick
- Ron Melnick Consulting, LLC, 274E 2280N, #B, North Logan, UT 84341, USA.
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34
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Surgical wound fluids from patients treated with intraoperative radiotherapy induce radiobiological response in breast cancer cells. Med Oncol 2018; 36:14. [PMID: 30599057 PMCID: PMC6312533 DOI: 10.1007/s12032-018-1243-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 12/24/2018] [Indexed: 12/24/2022]
Abstract
Breast cancer is the most common cancer occurring in women. The standard of breast cancer treatment is based on breast-conserving surgery with administration of adjuvant whole breast radiotherapy. Research shows that in-breast relapse is most likely to occur in the tumour bed, i.e. around the scar. Intraoperative radiotherapy (IORT), in which radiation is delivered to the tumour bed, reduces the risk of local recurrence not only through direct cell killing, but also through modification of local microenvironment. Additionally IORT modifies the composition and biological activity of surgical wound fluid. Since many researchers show that radiation damage is mediated through factors secreted to the environment by irradiated cells, we hypothesized that this radiation-induced bystander effect is partly responsible for the change observed in surgical wound fluids. We collected conditioned medium from irradiated breast cancer cells (CM) and surgical wound fluids from patients who underwent IORT (RT-WF) and from patients after breast-conserving surgery alone (WF). We incubated two breast cancer cell lines (MCF-7 and MDA-MB-468) with WF, RT-WF, CM or WF + CM and measured radiobiological response of cells. We measured the level of double-strand breaks, induction of apoptosis and the changes in expression of genes related to DNA damage repair. We observed that stimulation with RT-WF and with WF + CM-induced double-strand breaks and increased expression of DNA damage repair-related genes, which was not observed after stimulation with WF. These results suggest that IOERT induces secretion of bystander factors mediating the genotoxic effect of ionizing radiation.
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35
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Zhang L, Zeng H, Cheng WH. Beneficial and paradoxical roles of selenium at nutritional levels of intake in healthspan and longevity. Free Radic Biol Med 2018; 127:3-13. [PMID: 29782991 DOI: 10.1016/j.freeradbiomed.2018.05.067] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/15/2018] [Accepted: 05/17/2018] [Indexed: 11/15/2022]
Abstract
Accumulation of genome and macromolecule damage is a hallmark of aging, age-associated degeneration, and genome instability syndromes. Although processes of aging are irreversible, they can be modulated by genome maintenance pathways and environmental factors such as diet. Selenium (Se) confers its physiological functions mainly through selenoproteins, but Se compounds and other proteins that incorporate Se nonspecifically also impact optimal health. Bruce Ames proposed that the aging process could be mitigated by a subset of low-hierarchy selenoproteins whose levels are preferentially reduced in response to Se deficiency. Consistent with this notion, results from two selenotranscriptomic studies collectively implicate three low-hierarchy selenoproteins in age or senescence. Experimental evidence generally supports beneficial roles of selenoproteins in the protection against damage accumulation and redox imbalance, but some selenoproteins have also been reported to unexpectedly display harmful functions under sporadic conditions. While longevity and healthspan are usually thought to be projected in parallel, emerging evidence suggests a trade-off between longevity promotion and healthspan deterioration with damage accumulation. We propose that longevity promotion under conditions of Se deficiency may be attributed to 1) stress-response hormesis, an advantageous event of resistance to toxic chemicals at low doses; 2) reduced expression of selenoproteins with paradoxical functions to a lesser extent. In particular, selenoprotein H is an evolutionally conserved nuclear selenoprotein postulated to confer Se functions in redox regulation, genome maintenance, and senescence. This review highlights the need to pinpoint roles of specific selenoproteins and Se compounds in healthspan and lifespan for a better understanding of Se contribution at nutritional levels of intake to healthy aging.
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Affiliation(s)
- Li Zhang
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, MS 39762, USA
| | - Huawei Zeng
- USDA, Agricultural Research Service, Grand Forks Human Nutrition Center, Grand Forks, ND 58202, USA
| | - Wen-Hsing Cheng
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, MS 39762, USA.
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36
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Lee JS, Adler L, Karathia H, Carmel N, Rabinovich S, Auslander N, Keshet R, Stettner N, Silberman A, Agemy L, Helbling D, Eilam R, Sun Q, Brandis A, Malitsky S, Itkin M, Weiss H, Pinto S, Kalaora S, Levy R, Barnea E, Admon A, Dimmock D, Stern-Ginossar N, Scherz A, Nagamani SCS, Unda M, Wilson DM, Elhasid R, Carracedo A, Samuels Y, Hannenhalli S, Ruppin E, Erez A. Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures. Cell 2018; 174:1559-1570.e22. [PMID: 30100185 PMCID: PMC6225773 DOI: 10.1016/j.cell.2018.07.019] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 05/21/2018] [Accepted: 07/12/2018] [Indexed: 01/02/2023]
Abstract
The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed "UC dysregulation" (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response.
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Affiliation(s)
- Joo Sang Lee
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Lital Adler
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Hiren Karathia
- Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Narin Carmel
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Shiran Rabinovich
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Noam Auslander
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Rom Keshet
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Noa Stettner
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel; Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Alon Silberman
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Lilach Agemy
- Department of Plant and Environmental Science, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | | | - Raya Eilam
- Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Qin Sun
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexander Brandis
- Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sergey Malitsky
- Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Maxim Itkin
- Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Hila Weiss
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sivan Pinto
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Shelly Kalaora
- Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Ronen Levy
- Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Eilon Barnea
- Faculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel
| | - Arie Admon
- Faculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel
| | - David Dimmock
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Noam Stern-Ginossar
- Department of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Avigdor Scherz
- Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sandesh C S Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA
| | - Miguel Unda
- Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain; CIBERONC, Madrid, Spain
| | - David M Wilson
- Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA
| | - Ronit Elhasid
- Sackler Faculty of Medicine, Department of Pediatric Hemato Oncology, Sourasky Medical Center, Tel Aviv University, 6997801 Tel Aviv, Israel
| | - Arkaitz Carracedo
- CIBERONC, Madrid, Spain; CIC bioGUNE, Bizkaia Technology Park, 801 Building, 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain
| | - Yardena Samuels
- Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Sridhar Hannenhalli
- Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Eytan Ruppin
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA; Schools of Medicine and Computer Science, Tel Aviv University, 6997801 Tel Aviv, Israel.
| | - Ayelet Erez
- Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
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37
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Berger ND, Stanley FKT, Moore S, Goodarzi AA. ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0283. [PMID: 28847820 DOI: 10.1098/rstb.2016.0283] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2017] [Indexed: 12/14/2022] Open
Abstract
Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase with a master regulatory function in the DNA damage response. In this role, ATM commands a complex biochemical network that signals the presence of oxidative DNA damage, including the dangerous DNA double-strand break, and facilitates subsequent repair. Here, we review the current state of knowledge regarding ATM-dependent chromatin remodelling and epigenomic alterations that are required to maintain genomic integrity in the presence of DNA double-strand breaks and/or oxidative stress. We will focus particularly on the roles of ATM in adjusting nucleosome spacing at sites of unresolved DNA double-strand breaks within complex chromatin environments, and the impact of ATM on preserving the health of cells within the mammalian central nervous system.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.
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Affiliation(s)
- N Daniel Berger
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
| | - Fintan K T Stanley
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
| | - Shaun Moore
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
| | - Aaron A Goodarzi
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
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38
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Tao Y, Xie S, Xu F, Liu A, Wang Y, Chen D, Pan Y, Huang L, Peng D, Wang X, Yuan Z. Ochratoxin A: Toxicity, oxidative stress and metabolism. Food Chem Toxicol 2018; 112:320-331. [DOI: 10.1016/j.fct.2018.01.002] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/28/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023]
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39
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Cupello S, Richardson C, Yan S. Cell-free Xenopus egg extracts for studying DNA damage response pathways. THE INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY 2018; 60:229-236. [PMID: 27160070 DOI: 10.1387/ijdb.160113sy] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
In response to a variety of DNA replication stress or DNA damaging agents, the DNA damage response (DDR) pathways are triggered for cells to coordinate DNA repair, cell cycle checkpoints, apoptosis, and senescence. Cell-free Xenopus egg extracts, derived from the eggs of African clawed frogs (Xenopus laevis), have been widely used for studies concerning DDR pathways. In this review, we focus on how different experimental systems have been established using Xenopus egg extracts to investigate the DDR pathways that are activated in response to DNA replication stress, double-strand breaks (DSBs), inter-strand crosslinks (ICLs), and oxidative stress. We summarize how molecular details of DDR pathways are dissected by the mechanistic studies with Xenopus egg extracts. We also provide an update on the regulation of translesion DNA synthesis (TLS) polymerases (Pol ĸ and REV1) in the DDR pathways. A better understanding of DDR pathways using Xenopus egg extracts has opened new avenues for future cancer therapeutics. Finally, we offer our perspectives of future directions for studies of DDR pathways with Xenopus egg extracts.
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Affiliation(s)
- Steven Cupello
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA
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40
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Baruch-Torres N, Brieba LG. Plant organellar DNA polymerases are replicative and translesion DNA synthesis polymerases. Nucleic Acids Res 2017; 45:10751-10763. [PMID: 28977655 PMCID: PMC5737093 DOI: 10.1093/nar/gkx744] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 08/14/2017] [Indexed: 02/01/2023] Open
Abstract
Genomes acquire lesions that can block the replication fork and some lesions must be bypassed to allow survival. The nuclear genome of flowering plants encodes two family-A DNA polymerases (DNAPs), the result of a duplication event, that are the sole DNAPs in plant organelles. These DNAPs, dubbed Plant Organellar Polymerases (POPs), resemble the Klenow fragment of bacterial DNAP I and are not related to metazoan and fungal mitochondrial DNAPs. Herein we report that replicative POPs from the plant model Arabidopsis thaliana (AtPolI) efficiently bypass one the most insidious DNA lesions, an apurinic/apyrimidinic (AP) site. AtPolIs accomplish lesion bypass with high catalytic efficiency during nucleotide insertion and extension. Lesion bypass depends on two unique polymerization domain insertions evolutionarily unrelated to the insertions responsible for lesion bypass by DNAP θ, an analogous lesion bypass polymerase. AtPolIs exhibit an insertion fidelity that ranks between the fidelity of replicative and lesion bypass DNAPs, moderate 3′-5′ exonuclease activity and strong strand-displacement. AtPolIs are the first known example of a family-A DNAP evolved to function in both DNA replication and lesion bypass. The lesion bypass capabilities of POPs may be required to prevent replication fork collapse in plant organelles.
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Affiliation(s)
- Noe Baruch-Torres
- Langebio-Cinvestav Sede Irapuato, Km. 9.6 Libramiento Norte Carretera. Irapuato-León, 36821 Irapuato Guanajuato, México
| | - Luis G Brieba
- Langebio-Cinvestav Sede Irapuato, Km. 9.6 Libramiento Norte Carretera. Irapuato-León, 36821 Irapuato Guanajuato, México
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41
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Sun L, Nakajima S, Teng Y, Chen H, Yang L, Chen X, Gao B, Levine AS, Lan L. WRN is recruited to damaged telomeres via its RQC domain and tankyrase1-mediated poly-ADP-ribosylation of TRF1. Nucleic Acids Res 2017; 45:3844-3859. [PMID: 28158503 PMCID: PMC5397154 DOI: 10.1093/nar/gkx065] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 01/24/2017] [Indexed: 01/15/2023] Open
Abstract
Werner syndrome (WS) is a progeroid-like syndrome caused by WRN gene mutations. WS cells exhibit shorter telomere length compared to normal cells, but it is not fully understood how WRN deficiency leads directly to telomere dysfunction. By generating localized telomere-specific DNA damage in a real-time fashion and a dose-dependent manner, we found that the damage response of WRN at telomeres relies on its RQC domain, which is different from the canonical damage response at genomic sites via its HRDC domain. We showed that in addition to steady state telomere erosion, WRN depleted cells are also sensitive to telomeric damage. WRN responds to site-specific telomeric damage via its RQC domain, interacting at Lysine 1016 and Phenylalanine1037 with the N-terminal acidic domain of the telomere shelterin protein TRF1 and demonstrating a novel mechanism for WRN's role in telomere protection. We also found that tankyrase1-mediated poly-ADP-ribosylation of TRF1 is important for both the interaction between WRN and TRF1 and the damage recruitment of WRN to telomeres. Mutations of potential tankyrase1 ADP-ribosylation sites within the RGCADG motif of TRF1 strongly diminish the interaction with WRN and the damage response of WRN only at telomeres. Taken together, our results reveal a novel mechanism as to how WRN protects telomere integrity from damage and telomere erosion.
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Affiliation(s)
- Luxi Sun
- School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.,University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
| | - Satoshi Nakajima
- University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
| | - Yaqun Teng
- School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.,University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
| | - Hao Chen
- School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.,University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
| | - Lu Yang
- School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.,University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
| | - Xiukai Chen
- University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
| | - Boya Gao
- University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA
| | - Arthur S Levine
- University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
| | - Li Lan
- University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.,Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA
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Moore JM, Correa R, Rosenberg SM, Hastings PJ. Persistent damaged bases in DNA allow mutagenic break repair in Escherichia coli. PLoS Genet 2017; 13:e1006733. [PMID: 28727736 PMCID: PMC5542668 DOI: 10.1371/journal.pgen.1006733] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 08/03/2017] [Accepted: 04/03/2017] [Indexed: 12/31/2022] Open
Abstract
Bacteria, yeast and human cancer cells possess mechanisms of mutagenesis upregulated by stress responses. Stress-inducible mutagenesis potentially accelerates adaptation, and may provide important models for mutagenesis that drives cancers, host pathogen interactions, antibiotic resistance and possibly much of evolution generally. In Escherichia coli repair of double-strand breaks (DSBs) becomes mutagenic, using low-fidelity DNA polymerases under the control of the SOS DNA-damage response and RpoS general stress response, which upregulate and allow the action of error-prone DNA polymerases IV (DinB), II and V to make mutations during repair. Pol IV is implied to compete with and replace high-fidelity DNA polymerases at the DSB-repair replisome, causing mutagenesis. We report that up-regulated Pol IV is not sufficient for mutagenic break repair (MBR); damaged bases in the DNA are also required, and that in starvation-stressed cells, these are caused by reactive-oxygen species (ROS). First, MBR is reduced by either ROS-scavenging agents or constitutive activation of oxidative-damage responses, both of which reduce cellular ROS levels. The ROS promote MBR other than by causing DSBs, saturating mismatch repair, oxidizing proteins, or inducing the SOS response or the general stress response. We find that ROS drive MBR through oxidized guanines (8-oxo-dG) in DNA, in that overproduction of a glycosylase that removes 8-oxo-dG from DNA prevents MBR. Further, other damaged DNA bases can substitute for 8-oxo-dG because ROS-scavenged cells resume MBR if either DNA pyrimidine dimers or alkylated bases are induced. We hypothesize that damaged bases in DNA pause the replisome and allow the critical switch from high fidelity to error-prone DNA polymerases in the DSB-repair replisome, thus allowing MBR. The data imply that in addition to the indirect stress-response controlled switch to MBR, a direct cis-acting switch to MBR occurs independently of DNA breakage, caused by ROS oxidation of DNA potentially regulated by ROS regulators.
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Affiliation(s)
- Jessica M. Moore
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Raul Correa
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Susan M. Rosenberg
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
| | - P. J. Hastings
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
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Rangaswamy S, Pandey A, Mitra S, Hegde ML. Pre-Replicative Repair of Oxidized Bases Maintains Fidelity in Mammalian Genomes: The Cowcatcher Role of NEIL1 DNA Glycosylase. Genes (Basel) 2017; 8:E175. [PMID: 28665322 PMCID: PMC5541308 DOI: 10.3390/genes8070175] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 06/16/2017] [Accepted: 06/24/2017] [Indexed: 02/06/2023] Open
Abstract
Genomic fidelity in the humans is continuously challenged by genotoxic reactive oxygen species (ROS) generated both endogenously during metabolic processes, and by exogenous agents. Mispairing of most ROS-induced oxidized base lesions during DNA replication induces mutations. Although bulky base adducts induced by ultraviolet light and other environmental mutagens block replicative DNA polymerases, most oxidized base lesions do not block DNA synthesis. In 8-oxo-G:A mispairs generated by the incorporation of A opposite unrepaired 8-oxo-G, A is removed by MutYH (MYH) for post-replicative repair, and other oxidized base lesions must be repaired prior to replication in order to prevent mutation fixation. Our earlier studies documented S phase-specific overexpression of endonuclease VIII-like 1 (NEIL1) DNA glycosylase (DG), one of five oxidized base excision repair (BER)-initiating enzymes in mammalian cells, and its high affinity for replication fork-mimicking single-stranded (ss)DNA substrates. We recently provided experimental evidence for the role of NEIL1 in replicating-strand repair, and proposed the "cowcatcher" model of pre-replicative BER, where NEIL1's nonproductive binding to the lesion base in ssDNA template blocks DNA chain elongation, causing fork regression. Repair of the lesion in the then re-annealed duplex is carried out by NEIL1 in association with the DNA replication proteins. In this commentary, we highlight the critical role of pre-replicative BER in preventing mutagenesis, and discuss the distinction between pre-replicative vs. post-replicative BER.
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Affiliation(s)
- Suganya Rangaswamy
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
| | - Arvind Pandey
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
| | - Sankar Mitra
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
- Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
| | - Muralidhar L Hegde
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
- Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
- Houston Methodist Neurological Institute, Houston, TX 77030, USA.
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Crouch JD, Brosh RM. Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism. Free Radic Biol Med 2017; 107:245-257. [PMID: 27884703 PMCID: PMC5440220 DOI: 10.1016/j.freeradbiomed.2016.11.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 11/11/2016] [Accepted: 11/13/2016] [Indexed: 12/21/2022]
Abstract
Cells are under constant assault from reactive oxygen species that occur endogenously or arise from environmental agents. An important consequence of such stress is the generation of oxidatively damaged DNA, which is represented by a wide range of non-helix distorting and helix-distorting bulkier lesions that potentially affect a number of pathways including replication and transcription; consequently DNA damage tolerance and repair pathways are elicited to help cells cope with the lesions. The cellular consequences and metabolism of oxidatively damaged DNA can be quite complex with a number of DNA metabolic proteins and pathways involved. Many of the responses to oxidative stress involve a specialized class of enzymes known as helicases, the topic of this review. Helicases are molecular motors that convert the energy of nucleoside triphosphate hydrolysis to unwinding of structured polynucleic acids. Helicases by their very nature play fundamentally important roles in DNA metabolism and are implicated in processes that suppress chromosomal instability, genetic disease, cancer, and aging. We will discuss the roles of helicases in response to nuclear and mitochondrial oxidative stress and how this important class of enzymes help cells cope with oxidatively generated DNA damage through their functions in the replication stress response, DNA repair, and transcriptional regulation.
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Affiliation(s)
- Jack D Crouch
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD 21224, USA
| | - Robert M Brosh
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD 21224, USA.
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Bus JS. IARC use of oxidative stress as key mode of action characteristic for facilitating cancer classification: Glyphosate case example illustrating a lack of robustness in interpretative implementation. Regul Toxicol Pharmacol 2017; 86:157-166. [PMID: 28274811 DOI: 10.1016/j.yrtph.2017.03.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 02/28/2017] [Accepted: 03/02/2017] [Indexed: 11/27/2022]
Abstract
The International Agency for Research on Cancer (IARC) has formulated 10 key characteristics of human carcinogens to incorporate mechanistic data into cancer hazard classifications. The analysis used glyphosate as a case example to examine the robustness of IARC's determination of oxidative stress as "strong" evidence supporting a plausible cancer mechanism in humans. The IARC analysis primarily relied on 14 human/mammalian studies; 19 non-mammalian studies were uninformative of human cancer given the broad spectrum of test species and extensive use of formulations and aquatic testing. The mammalian studies had substantial experimental limitations for informing cancer mechanism including use of: single doses and time points; cytotoxic/toxic test doses; tissues not identified as potential cancer targets; glyphosate formulations or mixtures; technically limited oxidative stress biomarkers. The doses were many orders of magnitude higher than human exposures determined in human biomonitoring studies. The glyphosate case example reveals that the IARC evaluation fell substantially short of "strong" supporting evidence of oxidative stress as a plausible human cancer mechanism, and suggests that other IARC monographs relying on the 10 key characteristics approach should be similarly examined for a lack of robust data integration fundamental to reasonable mode of action evaluations.
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Affiliation(s)
- James S Bus
- Exponent, Inc., 1800 Diagonal Road, Suite 500, Alexandria, VA 22314, United States.
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Pandey PK, Ajima MNO, Kumar K, Poojary N, Kumar S. Evaluation of DNA damage and physiological responses in Nile tilapia, Oreochromis niloticus (Linnaeus, 1758) exposed to sub-lethal diclofenac (DCF). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2017; 186:205-214. [PMID: 28324828 DOI: 10.1016/j.aquatox.2017.03.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 03/03/2017] [Accepted: 03/04/2017] [Indexed: 06/06/2023]
Abstract
The frequent bioaccumulation of pharmaceuticals in the aquatic ecosystem has raised a concern about their possible ecotoxicological consequences. DNA damage, haematological changes and activities of oxidative stress enzymes in Nile tilapia, Oreochromis niloticus in response to diclofenac (DCF) exposure were investigated for up to 60 days at the concentrations of 0.17, 0.34 and 0.68mgL-1 in the fish liver. Evaluation of genotoxic effects of the drug in the liver, using single-cell gel electrophoresis, showed DNA damage on exposure at the concentrations of 0.34 and 0.68mgL-1 after day 30. Compared with the control, there was a reduction in haemoglobin and red blood cell counts with a significant increase (p<0.05) in white blood cell counts, mean corpuscular volume and mean corpuscular haemoglobin level after day 30 at 0.34 and 0.68mgL-1. The levels of pack cell volume, red cell distribution width and mean corpuscular haemoglobin concentration were not significant (p>0.05) between the exposed group and the control. The indices of hepatic oxidative stress biomarkers, including lipid peroxidation and carbonyl protein, showed elevated level, depicting a positive correlation with both time and concentration. More so, activity of catalase was inhibited while reduced glutathione level decreased in the liver tissue. There was increase in the activities of superoxide dismutase, glutathione peroxidase and glutathione-S-transferase after 30 days at 0.34mgL-1. Further, activity of Na+-K+-ATPase in the tissue was significantly inhibited (p<0.05) at the end of 60 days. Prolonged exposure to diclofenac at sub-lethal concentration can cause both DNA and oxidative damages in O. niloticus, suggesting the use of oxidative stress biomarkers as early warning signals in environmental monitoring of residual pharmaceutical and assessment.
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Affiliation(s)
- Pramod K Pandey
- College of Fisheries, Central Agriculture University, Agartala, Tripura, India
| | - Malachy N O Ajima
- Department of Fisheries and Aquaculture Technology, Federal University of Technology, Owerri, Nigeria; Aquatic Environment and Health Management Division, ICAR-Central Institute of Fisheries Education, Mumbai, India.
| | - Kundan Kumar
- Aquatic Environment and Health Management Division, ICAR-Central Institute of Fisheries Education, Mumbai, India
| | - Nalini Poojary
- Aquatic Environment and Health Management Division, ICAR-Central Institute of Fisheries Education, Mumbai, India
| | - Saurav Kumar
- Aquatic Environment and Health Management Division, ICAR-Central Institute of Fisheries Education, Mumbai, India
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Zhang X, Lu X, Akhter S, Georgescu MM, Legerski RJ. FANCI is a negative regulator of Akt activation. Cell Cycle 2017; 15:1134-43. [PMID: 27097374 DOI: 10.1080/15384101.2016.1158375] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Akt is a critical mediator of the oncogenic PI3K pathway, and its activation is regulated by kinases and phosphatases acting in opposition. We report here the existence of a novel protein complex that is composed minimally of Akt, PHLPP1, PHLPP2, FANCI, FANCD2, USP1 and UAF1. Our studies show that depletion of FANCI, but not FANCD2 or USP1, results in increased phosphorylation and activation of Akt. This activation is due to a reduction in the interaction between PHLPP1 and Akt in the absence of FANCI. In response to DNA damage or growth factor treatment, the interactions between Akt, PHLPP1 and FANCI are reduced consistent with the known phosphorylation of Akt in response to these stimuli. Furthermore, depletion of FANCI results in reduced apoptosis after DNA damage in accord with its role as a negative regular of Akt. Our findings describe an unexpected function for FANCI in the regulation of Akt and define a previously unrecognized intersection between the PI3K-Akt and FA pathways.
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Affiliation(s)
- Xiaoshan Zhang
- a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Xiaoyan Lu
- a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Shamima Akhter
- a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | | | - Randy J Legerski
- a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA
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Visible Light-Responsive Platinum-Containing Titania Nanoparticle-Mediated Photocatalysis Induces Nucleotide Insertion, Deletion and Substitution Mutations. NANOMATERIALS 2016; 7:nano7010002. [PMID: 28336836 PMCID: PMC5295192 DOI: 10.3390/nano7010002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 12/08/2016] [Accepted: 12/22/2016] [Indexed: 12/22/2022]
Abstract
Conventional photocatalysts are primarily stimulated using ultraviolet (UV) light to elicit reactive oxygen species and have wide applications in environmental and energy fields, including self-cleaning surfaces and sterilization. Because UV illumination is hazardous to humans, visible light-responsive photocatalysts (VLRPs) were discovered and are now applied to increase photocatalysis. However, fundamental questions regarding the ability of VLRPs to trigger DNA mutations and the mutation types it elicits remain elusive. Here, through plasmid transformation and β-galactosidase α-complementation analyses, we observed that visible light-responsive platinum-containing titania (TiO2) nanoparticle (NP)-mediated photocatalysis considerably reduces the number of Escherichia coli transformants. This suggests that such photocatalytic reactions cause DNA damage. DNA sequencing results demonstrated that the DNA damage comprises three mutation types, namely nucleotide insertion, deletion and substitution; this is the first study to report the types of mutations occurring after photocatalysis by TiO2-VLRPs. Our results may facilitate the development and appropriate use of new-generation TiO2 NPs for biomedical applications.
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Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance. Cancer Lett 2016; 386:87-99. [PMID: 27867017 DOI: 10.1016/j.canlet.2016.11.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/25/2016] [Accepted: 11/10/2016] [Indexed: 01/06/2023]
Abstract
Radio (chemo) therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC), but relapse is frequent, and the underlying mechanisms remain largely elusive. Therefore, novel biomarkers are urgently needed. Previously, we identified gains on 16q23-24 to be associated with amplification of the Fanconi anemia A (FancA) gene and to correlate with reduced progression-free survival after radiotherapy. Here, we analyzed the effects of FancA on radiation sensitivity in vitro, characterized the underlying mechanisms, and evaluated their clinical relevance. Silencing of FancA expression in HNSCC cell lines with genomic gains on 16q23-24 resulted in significantly impaired clonogenic survival upon irradiation. Conversely, overexpression of FancA in immortalized keratinocytes conferred increased survival accompanied by improved DNA repair, reduced accumulation of chromosomal translocations, but no hyperactivation of the FA/BRCA-pathway. Downregulation of interferon signaling as identified by microarray analyses, enforced irradiation-induced senescence, and elevated production of the senescence-associated secretory phenotype (SASP) appeared to be candidate mechanisms contributing to FancA-mediated radioresistance. Data of the TCGA HNSCC cohort confirmed the association of gains on 16q24.3 with FancA overexpression and impaired overall survival. Importantly, transcriptomic alterations similar to those observed upon FancA overexpression in vitro strengthened the clinical relevance. Overall, FancA amplification and overexpression appear to be crucial for radiotherapeutic failure in HNSCC.
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Benzyl isothiocyanate promotes apoptosis of oral cancer cells via an acute redox stress-mediated DNA damage response. Food Chem Toxicol 2016; 97:336-345. [DOI: 10.1016/j.fct.2016.09.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 09/19/2016] [Accepted: 09/26/2016] [Indexed: 11/24/2022]
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