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Işıksaçan N, Adaş G, Kasapoğlu P, Çukurova Z, Yılmaz R, Kurt Yaşar K, Irmak Koyuncu D, Tuncel FC, Şahingöz Erdal G, Gedikbaşı A, Pehlivan S, Karaoz E. The effect of mesenchymal stem cells administration on DNA repair gene expressions in critically ill COVID-19 patients: prospective controlled study. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024; 43:1431-1446. [PMID: 38459810 DOI: 10.1080/15257770.2024.2327478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/10/2024]
Abstract
When the studies are evaluated, immunomodulatory effect of MSCs, administration in critically ill patients, obstacle situations in use and side effects, pulmonary fibrosis prevention, which stem cells and their products, regeneration effect, administration route, and dosage are listed under the main heading like. The effect of MSC administration on DNA repair genes in COVID-19 infection is unknown. Our aim is to determine the effect of mesenchymal stem cells (MSCs) therapy applied in critically ill patients with coronavirus infection on DNA repair pathways and genes associated with those pathways. Patients (n = 30) divided into two equal groups. Group-1: Patients in a critically ill condition, Group-2: Patients in critically ill condition and transplanted MSCs. The mechanism was investigated in eleven genes of five different pathways; Base excision repair: PARP1, Nucleotide excision repair (NER): RAD23B and ERCC1, Homologous recombinational repair (HR): ATM, RAD51, RAD52 and WRN, Mismatch repair (MMR): MLH1, MSH2, and MSH6, Direct reversal repair pathway: MGMT. It was found that MSCs application had a significant effect on 6 genes located in 3 different DNA damage response pathways. These are NER pathway genes; RAD23 and ERCC1, HR pathway genes; ATM and RAD51, MMR pathway genes; MSH2 and MSH6 (p < 0.05). Two main points were shown. First, as a result of cellular damage in critical patients with COVID-19, DNA damage occurs and then DNA repair pathways and genes are activated in reaction to this situation. Second, administration of MSC to patients with COVID-19 infection plays a positive role by increasing the expression of DNA repair genes located in DNA damage pathways.
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Affiliation(s)
- Nilgün Işıksaçan
- Department of Biochemistry, Bakırköy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Gökhan Adaş
- Stem Cell And Gene Therapies Application And Research Center, Department Of Surgery, Bakırköy Dr. Sadi Konuk Training And Research Hospital, University Of Health Sciences, Istanbul, Turkey
| | - Pınar Kasapoğlu
- Department of Biochemistry, Bakırköy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Zafer Çukurova
- Department of Anesthesia and Intensive Care, Bakırköy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Rabia Yılmaz
- Department of Anesthesia and Intensive Care, Bakırköy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Kadriye Kurt Yaşar
- Department of Infectious Disease, Istanbul Bakırköy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey
| | - Duygu Irmak Koyuncu
- Center of Stem Cells and Tissue Engineering Research & Practice, Istinye University, Istanbul, Turkey
| | - Fatima Ceren Tuncel
- Department of Medical Biology Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Gülçin Şahingöz Erdal
- Department of Oncology, Bakırköy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Asuman Gedikbaşı
- Department of Pediatric Basic Science, Division of Medical Genetics, Institute of Child Health, Istanbul University, Istanbul, Turkey
| | - Sacide Pehlivan
- Department of Medical Biology Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Erdal Karaoz
- Department of Histology & Embrology, Faculty of Medicine, Istinye University, LIV Hospital, Center of Regenerative Medicine and Stem Cell Manufacturing, Istanbul, Turkey
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Volodina OV, Fabrichnikova AR, Anuchina AA, Mishina OS, Lavrov AV, Smirnikhina SA. Evolution of Prime Editing Systems: Move Forward to the Treatment of Hereditary Diseases. Curr Gene Ther 2024; 25:46-61. [PMID: 38623982 DOI: 10.2174/0115665232295117240405070809] [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: 01/04/2024] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 04/17/2024]
Abstract
The development of gene therapy using genome editing tools recently became relevant. With the invention of programmable nucleases, it became possible to treat hereditary diseases due to introducing targeted double strand break in the genome followed by homology directed repair (HDR) or non-homologous end-joining (NHEJ) reparation. CRISPR-Cas9 is more efficient and easier to use in comparison with other programmable nucleases. To improve the efficiency and safety of this gene editing tool, various modifications CRISPR-Cas9 basis were created in recent years, such as prime editing - in this system, Cas9 nickase is fused with reverse transcriptase and guide RNA, which contains a desired correction. Prime editing demonstrates equal or higher correction efficiency as HDR-mediated editing and much less off-target effect due to inducing nick. There are several studies in which prime editing is used to correct mutations in which researchers reported little or no evidence of off-target effects. The system can also be used to functionally characterize disease variants. However, prime editing still has several limitations that could be further improved. The effectiveness of the method is not yet high enough to apply it in clinical trials. Delivery of prime editors is also a big challenge due to their size. In the present article, we observe the development of the platform, and discuss the candidate proteins for efficiency enhancing, main delivery methods and current applications of prime editing.
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Affiliation(s)
- Olga V Volodina
- Laboratory of Genome Editing, Research Centre for Medical Genetics, 115522, Moscow, Russia
| | | | - Arina A Anuchina
- Laboratory of Genome Editing, Research Centre for Medical Genetics, 115522, Moscow, Russia
| | - Olesya S Mishina
- Laboratory of Genome Editing, Research Centre for Medical Genetics, 115522, Moscow, Russia
| | - Alexander V Lavrov
- Laboratory of Genome Editing, Research Centre for Medical Genetics, 115522, Moscow, Russia
| | - Svetlana A Smirnikhina
- Laboratory of Genome Editing, Research Centre for Medical Genetics, 115522, Moscow, Russia
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A Pan-Cancer Analysis on the Systematic Correlation of MutS Homolog 2 (MSH2) to a Malignant Tumor. JOURNAL OF ONCOLOGY 2022; 2022:9175402. [PMID: 35368899 PMCID: PMC8970884 DOI: 10.1155/2022/9175402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/02/2022] [Accepted: 03/04/2022] [Indexed: 11/18/2022]
Abstract
MutS homolog 2 (MSH2) is a crucial participant in human DNA repair, and lots of the studies functionally associated with it were begun with hereditary nonpolyposis colorectal cancer (HNPCC). MSH2 has also been reported to take part in the progresses of various tumors' formation. With the help of GTEx, CCLE, and TCGA pan-cancer databases, the analysis of MSH2 gene distribution in both tumor tissues and normal control tissues was carried out. Kaplan-Meyer survival plots and COX regression analysis were conducted for the assessment into the MSH2's impact on tumor patients' clinical prognosis. In an investigation to the association of MSH2 expression with immune infiltration level of various tumors and a similar study on tumor immune neoantigens, microsatellite instability was subsequently taken. It was found that high expression of MSH2 is prevalent in most cancers. MSH2's efficacy on clinical prognosis as well as immune infiltration in tumor patients revealed a fact that expression of MSH2 in prostate adenocarcinoma (PRAD), brain lower-grade glioma (LGG), breast-invasive carcinoma (BRCA), and head and neck squamous cell carcinoma (HNSC) posed a significant correlation with the immune cell infiltration level of patients. Likewise as above, MSH2's expression comes in a similar trend with tumor immune neoantigens and microsatellite instability. MSH2's expression in the majority of tumors is a direct factor to the activation of tumor-associated pathways as well as immune-associated pathways. MSH2's early screening or even therapeutic target role for sarcoma (SARC) diagnosis is contributing to the efficiency of early screening and overall survival in SARC patients.
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Understanding the genetic basis for cholangiocarcinoma. Adv Cancer Res 2022; 156:137-165. [DOI: 10.1016/bs.acr.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Analysis of the Expression and Prognostic Value of MSH2 in Pan-Cancer Based on Bioinformatics. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9485273. [PMID: 34859104 PMCID: PMC8632401 DOI: 10.1155/2021/9485273] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/06/2021] [Indexed: 12/30/2022]
Abstract
Background MutS homolog 2 (MSH2), with the function of identifying mismatches and participating in DNA repair, is the “housekeeping gene” in the mismatch repair (MMR) system. MSH2 deficiency has been reported to enhance cancer susceptibility for the association of hereditary nonpolyposis colorectal cancer. However, the expression and prognostic significance of MSH2 have not been studied from the perspective of pan-cancer. Methods The GTEx database was used to analyze the expression of MSH2 in normal tissues. The TCGA database was used to analyze the differential expression of MSH2 in pan-cancers. The prognostic value of MSH2 in pan-cancer was assessed using Cox regression and Kaplan-Meier analysis. Spearman correlations were used to measure the relationship between the expression level of MSH2 in pan-cancer and the level of immune infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI). Results MSH2 is highly expressed in most type of cancers and significantly correlated with prognosis. In COAD, KIRC, LIHC, and SKCM, the expression of MSH2 was significantly positively correlated with the abundance of B cells, CD4+ T cells, CD8+ T cells, dendritic cells, macrophages, and neutrophils. In THCA, MSH2 expression correlated with CD8+T Cell showed a significant negative correlation. MSH2 had significantly negative correlations with stromal score and immune score in a variety of cancers and significantly correlated with TMB and MSI of a variety of tumors. Conclusions MSH2 may play an important role in the occurrence, development, and immune infiltration of cancer. MSH2 can emerge as a potential biomarker for cancer diagnosis and prognosis.
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Tedjasaputra TR, Hatta M, Massi MN, Natzir R, Bukhari A, Masadah R, Parewangi ML, Prihantono P, Nariswati R, Tedjasaputra V. Prediction of hereditary nonpolyposis colorectal cancer using mRNA MSH2 quantitative and the correlation with nonmodifiable factor. World J Gastrointest Pathophysiol 2021; 12:130-142. [DOI: 10.4291/wjgp.v12.i6.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Tjahjadi Robert Tedjasaputra
- Department of Internal Medicine, Tarakan General Hospital, Medical Faculty University of Hasanuddin, Jakarta 10720, DKI Jakarta, Indonesia
| | - Mochammad Hatta
- Department of Immunology and Biomolecular, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Muh Nasrum Massi
- Department of Microbiology, Faculty of Medicine, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Rosdiana Natzir
- Department of Biochemistry Meidcal Faculty, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Agussalim Bukhari
- Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rina Masadah
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Muh Lutfi Parewangi
- Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Prihantono Prihantono
- Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rinda Nariswati
- Department of Statistic, School of Computer Science, Bina Nusantara University Jakarta, Jakarta 11530, Indonesia
| | - Vincent Tedjasaputra
- American Association for the Advancement of Science (AAAS), Science and Technology Policy Fellow, Alexandria, VA 22314, United States
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Tedjasaputra TR, Hatta M, Massi MN, Natzir R, Bukhari A, Masadah R, Parewangi ML, Prihantono P, Nariswati R, Tedjasaputra V. Prediction of hereditary nonpolyposis colorectal cancer using mRNA MSH2 quantitative and the correlation with nonmodifiable factor. World J Gastrointest Pathophysiol 2021; 12:134-146. [PMID: 34877027 PMCID: PMC8611184 DOI: 10.4291/wjgp.v12.i6.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/13/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hereditary non-polyposis colon cancer is a dominantly inherited syndrome of colorectal cancer (CRC), with heightened risk for younger population. Previous studies link its susceptibility to the DNA sequence polymorphism along with Amsterdam and Bethesda criteria. However, those fail in term of applicability. AIM To determine a clear cut-off of MSH2 gene expression for CRC heredity grouping factor. Further, the study also aims to examine the association of risk factors to the CRC heredity. METHODS The cross-sectional study observed 71 respondents from May 2018 to December 2019 in determining the CRC hereditary status through MSH2 mRNA expression using reverse transcription-polymerase chain reaction and the disease's risk factors. Data were analyzed through Chi-Square, Fischer exact, t-test, Mann-Whitney, and multiple logistics. RESULTS There are significant differences of MSH2 within CRC group among tissue and blood; yet, negative for significance between groups. Through the blood gene expression fifth percentile, the hereditary CRC cut-off is 11059 fc, dividing the 40 CRC respondents to 32.5% with hereditary CRC. Significant risk factors include age, family history, and staging. Nonetheless, after multivariate control, age is just a confounder. Further, the study develops a probability equation with area under the curve 82.2%. CONCLUSION Numerous factors have significant relations to heredity of CRC patients. However, true important factors are staging and family history, while age and others are confounders. The study also established a definite cut-off point for heredity CRC based on mRNA MSH2 expression, 11059 fc. These findings shall act as concrete foundations on further risk factors and/or genetical CRC future studies.
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Affiliation(s)
- Tjahjadi Robert Tedjasaputra
- Department of Internal Medicine, Tarakan General Hospital, Medical Faculty University of Hasanuddin, Jakarta 10720, DKI Jakarta, Indonesia
| | - Mochammad Hatta
- Department of Immunology and Biomolecular, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Muh Nasrum Massi
- Department of Microbiology, Faculty of Medicine, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Rosdiana Natzir
- Department of Biochemistry Meidcal Faculty, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Agussalim Bukhari
- Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rina Masadah
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Muh Lutfi Parewangi
- Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Prihantono Prihantono
- Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rinda Nariswati
- Department of Statistic, School of Computer Science, Bina Nusantara University Jakarta, Jakarta 11530, Indonesia
| | - Vincent Tedjasaputra
- American Association for the Advancement of Science (AAAS), Science and Technology Policy Fellow, Alexandria, VA 22314, United States
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Si J, Huang B, Lan G, Zhang B, Wei J, Deng Z, Li Y, Qin Y, Li B, Lu Y, Si Y. Comparison of whole exome sequencing in circulating tumor cells of primitive and metastatic nasopharyngeal carcinoma. Transl Cancer Res 2020; 9:4080-4092. [PMID: 35117778 PMCID: PMC8798411 DOI: 10.21037/tcr-19-2899] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 06/03/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is one of the most common cancers. To investigate the gene mutation profile of NPC patients, we performed whole exome sequencing (WES) in tumor cells, peripheral blood cells, and circulating tumor cells (CTCs) of primitive and metastatic NPC patients, and explored its clinical significance. METHODS Primitive tumor cells, white blood cells, and CTCs of patients were collected and hybridized with probes targeting whole exons. Mutational signatures, signaling pathways, and cancer associated genes from CTCs cells of two primitive and two metastatic patients were analyzed using gene ontology (GO) method. RESULTS The mutational landscape of four primitive tumors showed that there were more MSH2 alterations in more non-silent mutation number patients Additionally, BAP1 gene mutation only occurred in metastatic patients. The most frequently mutated genes among the primitive tumor and CTC samples were CFAP74, MOB3C, PDE4DIP, IGFN1, CYFIP2, NOP16, SLC22A1, ZNF117, and SSPO. Interestingly, only PMS1, BRIP1, DEE, OR2T12, CPN2, MLXIPL, BAIAP3, IGSF3, SIN3B, and ZNF880 alterations occurred in primary tumors of metastatic patients. Primitive and metastatic NPC had significantly distinct mutational signatures. GO analysis revealed that each patient had his own mutational signaling pathways. Non-silent single nucleotide variations (non-silent SNVs) and insertion-deletion mutations (INDELs) in CTCs were more dramatic than in primitive tumor cells. CONCLUSIONS These changes are strongly relevant to their clinical characteristics and therapeutic strategy.
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Affiliation(s)
- Jinyuan Si
- Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Bo Huang
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Guiping Lan
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Benjian Zhang
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jiazhang Wei
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Zhuoxia Deng
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yiliang Li
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Ying Qin
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Bing Li
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yan Lu
- SurExam Bio-Techs, Guangzhou Technology Innovation Base, Guangzhou, China
| | - Yongfeng Si
- Department of Otolaryngology-Head and Neck Oncology, and Nasopharyngeal Carcinoma Institute, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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Thirumal Kumar D, Susmita B, Judith E, Priyadharshini Christy J, George Priya Doss C, Zayed H. Elucidating the role of interacting residues of the MSH2-MSH6 complex in DNA repair mechanism: A computational approach. DNA Repair (Amst) 2019; 115:325-350. [DOI: 10.1016/bs.apcsb.2018.11.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Comparative genomic investigation of high-elevation adaptation in ectothermic snakes. Proc Natl Acad Sci U S A 2018; 115:8406-8411. [PMID: 30065117 DOI: 10.1073/pnas.1805348115] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Several previous genomic studies have focused on adaptation to high elevations, but these investigations have been largely limited to endotherms. Snakes of the genus Thermophis are endemic to the Tibetan plateau and therefore present an opportunity to study high-elevation adaptations in ectotherms. Here, we report the de novo assembly of the genome of a Tibetan hot-spring snake (Thermophis baileyi) and then compare its genome to the genomes of the other two species of Thermophis, as well as to the genomes of two related species of snakes that occur at lower elevations. We identify 308 putative genes that appear to be under positive selection in Thermophis We also identified genes with shared amino acid replacements in the high-elevation hot-spring snakes compared with snakes and lizards that live at low elevations, including the genes for proteins involved in DNA damage repair (FEN1) and response to hypoxia (EPAS1). Functional assays of the FEN1 alleles reveal that the Thermophis allele is more stable under UV radiation than is the ancestral allele found in low-elevation lizards and snakes. Functional assays of EPAS1 alleles suggest that the Thermophis protein has lower transactivation activity than the low-elevation forms. Our analysis identifies some convergent genetic mechanisms in high-elevation adaptation between endotherms (based on studies of mammals) and ectotherms (based on our studies of Thermophis).
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Liu C, Chang H, Li XH, Qi YF, Wang JO, Zhang Y, Yang XH. Network Meta-Analysis on the Effects of DNA Damage Response-Related Gene Mutations on Overall Survival of Breast Cancer Based on TCGA Database. J Cell Biochem 2017; 118:4728-4734. [PMID: 28513990 DOI: 10.1002/jcb.26140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 05/16/2017] [Indexed: 01/04/2023]
Abstract
The study was conducted for comparing the effects of 12 DNA damage response gene mutations (CHEK1, CHEK2, RAD51, BRCA1, BRCA2, MLH1, MSH2, ATM, ATR, MDC1, PARP1, and FANCF) on the overall survival (OS) of breast cancer (BC) patients. We searched the Cancer Genome Atlas (TCGA) database from inception to September 2016. Studies that investigated the association between 12 DNA damage responses related genes and BC consolidated into this Network meta-analysis, by comparing directly or indirectly to evaluate the hazard rate (HR) value and the surface under the cumulative sequence ranking curves (SUCRA). In total four articles were involved. Our results demonstrated 12 DNA damage response gene mutations were associated to the poor prognosis of BC patients (CHEK1: HR = 9.9, 95%CI = 3.6-26.0; CHEK2: HR = 6.9, 95%CI = 3.1-15.0; RAD51: HR = 5.8, 95%CI = 2.2-15.0; BRCA1: HR = 2.8, 95%CI = 1.3-6.1; BRCA2: HR = 3.9, 95%CI = 2.0-7.7; MLH1: HR = 11.0, 95%CI = 3.4-33.0; MSH2: HR = 6.5, 95%CI = 2.1-20.0; ATM: HR = 5.6, 95%CI = 2.6-12.0; ATR: HR = 2.9, 95%CI = 1.3-6.9; MDC1: HR = 15.0, 95%CI = 5.0-45.0; PARP1: HR = 3.4, 95%CI = 1.8-6.6; FANCF: HR = 6.0, 95%CI = 1.8-20.0). SUCRA results revealed that the mutation of MDC1 gene was related to the worst prognosis in patients with BC (SUCRA = 17.32%). DNA damage response gene mutations were associated to the poor prognosis in patients with BC and the BC patients with MDC1 gene mutation had the worst prognosis. J. Cell. Biochem. 118: 4728-4734, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Chang Liu
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China
| | - Hong Chang
- Department of Ophthalmology, Shenyang the Fourth Hospital of People, Shenyang, 110031, P. R. China
| | - Xiao-Han Li
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China
| | - Ya-Fei Qi
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China
| | - Jin-Ou Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China
| | - Ying Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China
| | - Xiang-Hong Yang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China
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Melnik BC. MiR-21: an environmental driver of malignant melanoma? J Transl Med 2015; 13:202. [PMID: 26116372 PMCID: PMC4482047 DOI: 10.1186/s12967-015-0570-5] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Accepted: 06/10/2015] [Indexed: 01/04/2023] Open
Abstract
Since the mid-1950’s, melanoma incidence has been rising steadily in industrialized Caucasian populations, thereby pointing to the pivotal involvement of environmental factors in melanomagenesis. Recent evidence underlines the crucial role of microRNA (miR) signaling in cancer initiation and progression. Increased miR-21 expression has been observed during the transition from a benign melanocytic lesion to malignant melanoma, exhibiting highest expression of miR-21. Notably, common BRAF and NRAS mutations in cutaneous melanoma are associated with increased miR-21 expression. MiR-21 is an oncomiR that affects critical target genes of malignant melanoma, resulting in sustained proliferation (PTEN, PI3K, Sprouty, PDCD4, FOXO1, TIPE2, p53, cyclin D1), evasion from apoptosis (FOXO1, FBXO11, APAF1, TIMP3, TIPE2), genetic instability (MSH2, FBXO11, hTERT), increased oxidative stress (FOXO1), angiogenesis (PTEN, HIF1α, TIMP3), invasion and metastasis (APAF1, PTEN, PDCD4, TIMP3). The purpose of this review is to provide translational evidence for major environmental and individual factors that increase the risk of melanoma, such as UV irradiation, chemical noxes, air pollution, smoking, chronic inflammation, Western nutrition, obesity, sedentary lifestyle and higher age, which are associated with increased miR-21 signaling. Exosomal miR-21 induced by extrinsic and intrinsic stimuli may be superimposed on mutation-induced miR-21 pathways of melanoma cells. Thus, oncogenic miR-21 signaling may be the converging point of intrinsic and extrinsic stimuli driving melanomagenesis. Future strategies of melanoma treatment and prevention should thus aim at reducing the burden of miR-21 signal transduction.
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Affiliation(s)
- Bodo C Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, 49090, Osnabrück, Germany.
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Karageorgos I, Mizzi C, Giannopoulou E, Pavlidis C, Peters BA, Zagoriti Z, Stenson PD, Mitropoulos K, Borg J, Kalofonos HP, Drmanac R, Stubbs A, van der Spek P, Cooper DN, Katsila T, Patrinos GP. Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach. Hum Genomics 2015; 9:12. [PMID: 26092435 PMCID: PMC4499216 DOI: 10.1186/s40246-015-0034-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Accepted: 06/11/2015] [Indexed: 11/29/2022] Open
Abstract
Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance.
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Affiliation(s)
- Ioannis Karageorgos
- Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece
| | - Clint Mizzi
- Department of Physiology and Biochemistry, Faculty of Health Sciences, University of Malta, Msida, Malta.,Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Efstathia Giannopoulou
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patras, Greece
| | - Cristiana Pavlidis
- Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece
| | - Brock A Peters
- Complete Genomics Inc., Mountain View, CA, USA.,BGI-Shenzhen, Shenzhen, 51803, China
| | - Zoi Zagoriti
- Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece
| | - Peter D Stenson
- Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | | | - Joseph Borg
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta.,Department of Cell Biology and Genetics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Haralabos P Kalofonos
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patras, Greece
| | - Radoje Drmanac
- Complete Genomics Inc., Mountain View, CA, USA.,BGI-Shenzhen, Shenzhen, 51803, China
| | - Andrew Stubbs
- Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Peter van der Spek
- Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - David N Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Theodora Katsila
- Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece
| | - George P Patrinos
- Department of Pharmacy, University of Patras, School of Health Sciences, University Campus, Rion GR-26504, Patras, Greece. .,Department of Bioinformatics, School of Medicine and Health Sciences, Erasmus University Medical Center, Rotterdam, The Netherlands.
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15
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Li Y, Melnikov AA, Levenson V, Guerra E, Simeone P, Alberti S, Deng Y. A seven-gene CpG-island methylation panel predicts breast cancer progression. BMC Cancer 2015; 15:417. [PMID: 25986046 PMCID: PMC4438505 DOI: 10.1186/s12885-015-1412-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 05/01/2015] [Indexed: 12/31/2022] Open
Abstract
Background DNA methylation regulates gene expression, through the inhibition/activation of gene transcription of methylated/unmethylated genes. Hence, DNA methylation profiling can capture pivotal features of gene expression in cancer tissues from patients at the time of diagnosis. In this work, we analyzed a breast cancer case series, to identify DNA methylation determinants of metastatic versus non-metastatic tumors. Methods CpG-island methylation was evaluated on a 56-gene cancer-specific biomarker microarray in metastatic versus non-metastatic breast cancers in a multi-institutional case series of 123 breast cancer patients. Global statistical modeling and unsupervised hierarchical clustering were applied to identify a multi-gene binary classifier with high sensitivity and specificity. Network analysis was utilized to quantify the connectivity of the identified genes. Results Seven genes (BRCA1, DAPK1, MSH2, CDKN2A, PGR, PRKCDBP, RANKL) were found informative for prognosis of metastatic diffusion and were used to calculate classifier accuracy versus the entire data-set. Individual-gene performances showed sensitivities of 63–79 %, 53–84 % specificities, positive predictive values of 59–83 % and negative predictive values of 63–80 %. When modelled together, these seven genes reached a sensitivity of 93 %, 100 % specificity, a positive predictive value of 100 % and a negative predictive value of 93 %, with high statistical power. Unsupervised hierarchical clustering independently confirmed these findings, in close agreement with the accuracy measurements. Network analyses indicated tight interrelationship between the identified genes, suggesting this to be a functionally-coordinated module, linked to breast cancer progression. Conclusions Our findings identify CpG-island methylation profiles with deep impact on clinical outcome, paving the way for use as novel prognostic assays in clinical settings. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1412-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yan Li
- Rush University Medical Center, 653 W Congress Pkwy, Chicago, IL, 60612, USA.
| | | | - Victor Levenson
- US Biomarkers, Inc, 29 Buckingham Ln., Buffalo Grove, IL, 60089, USA. .,Currently at Center for Translational Research, Catholic Health Initiatives, Englewood, USA.
| | - Emanuela Guerra
- Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy.
| | - Pasquale Simeone
- Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy.
| | - Saverio Alberti
- Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy. .,Department of Neuroscience, Imaging and Clinical Sciences, Unit of Physiology and Physiopathology, 'G. d'Annunzio' University, Via dei Vestini, 66100, Chieti, Italy.
| | - Youping Deng
- Rush University Medical Center, 653 W Congress Pkwy, Chicago, IL, 60612, USA.
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16
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Kanth VVR, Bhalsing S, Sasikala M, Rao GV, Pradeep R, Avanthi US, Reddy DN. Microsatellite instability and promoter hypermethylation in colorectal cancer in India. Tumour Biol 2014; 35:4347-4355. [PMID: 24408015 DOI: 10.1007/s13277-013-1570-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 12/17/2013] [Indexed: 12/01/2022] Open
Abstract
Microsatellite instability (MSI) is an important factor in tumor development and is a hypermutable phenotype caused by the loss of DNA mismatch repair activity. It is important to identify tumors with microsatellite instability as the patients have a better prognosis and differ with response to chemotherapy. Limited data are available on the incidence of MSI in Indian colorectal cancers (CRCs). The objectives of this study were to identify the extent of MSI in Indian CRC patients below 50 years and to determine promoter methylation status of hMLH1 and hMSH2 in relation to MSI. A total of 450 patients were diagnosed with CRC, out of which 91 individuals were recruited as per Bethesda guidelines and were tested for instability by the NCI-recommended Bethesda panel (BAT25, BAT26, D2S123, D5S346, and D17S2720) using labeled primers. The fragments were separated and analyzed on a Beckman GeXP sequencer. Promoter methylation status was determined by restriction enzyme digestion and PCR. MSI (high and low) was seen in 48.4% (44/91) of CRC patients, out of which microsatellite instability-high (MSI-H) was detected in 13.2% (12/91) and microsatellite instability-low (MSI-L) in 35.2% (32/91) and the rest were microsatellite stable (MSS), 51.6% (47/91). Majority of the MSI-H tumors were adenocarcinomas (10/12), in the rectum (8/12), and moderately or poorly differentiated (12/12). Promoter hypermethylation was seen in 75% of the MSI-H, 56.24% of MSI-L, and only 23.4% of MSS individuals. MSI (high and low) was associated with 48.4% of CRC patients, and a significantly higher proportion of promoter hypermethylation of hMLH1 and hMSH2 genes was associated with instable tumors.
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17
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Fan L, Niu Y, Zhang S, Shi L, Guo H, Liu Y, Zhang R. Development of a screening system for DNA damage and repair of potential carcinogens based on dual luciferase assay in human HepG2 cell. Mutagenesis 2013; 28:515-24. [DOI: 10.1093/mutage/get028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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18
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Leach DM, Zacal NJ, Rainbow AJ. Host cell reactivation of gene expression for an adenovirus-encoded reporter gene reflects the repair of UVC-induced cyclobutane pyrimidine dimers and methylene blue plus visible light-induced 8-oxoguanine. Mutagenesis 2013; 28:507-13. [PMID: 23793457 DOI: 10.1093/mutage/get027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Previously, we have reported the use of a recombinant adenovirus (Ad)-based host cell reactivation (HCR) assay to examine nucleotide excision repair (NER) of UVC-induced DNA lesions in several mammalian cell types. The recombinant non-replicating Ad expresses the Escherichia coli β-galactosidase (β-gal) reporter gene under control of the cytomegalovirus immediate-early enhancer region. We have also used methylene blue plus visible light (MB + VL) to induce the major oxidative lesion 7,8-dihydro-8-oxoguanine (8-oxoG) in the recombinant Ad-encoded reporter gene in order to study base excision repair (BER). The reported variability regarding 8-oxoG's potential to block transcription by RNA polymerase II and data demonstrating that a number of factors play a role in transcriptional bypass of the lesion led us to examine the repair of 8-oxoG in the Ad reporter and its relationship to HCR for expression of the reporter gene. We have used Southern blotting to examine removal of UVC- and MB + VL-induced DNA damage by loss of endonuclease-sensitive sites from the Ad-encoded β-gal reporter gene in human and rodent cells. We show that repair of MB + VL-induced 8-oxoG via BER and UVC-induced cyclobutane pyrimidine dimers (CPDs) via NER is substantially greater in human SV40-transformed GM637F skin fibroblasts compared to hamster CHO-AA8 cells. We also show that HCR for expression of the MB + VL-damaged and the UVC-damaged reporter gene is substantially greater in human SV40-transformed GM637F skin fibroblasts compared to hamster CHO-AA8 cells. The difference between the human and rodent cells in the removal of both 8-oxoG and CPDs from the damaged reporter gene was comparable to the difference in HCR for expression of the damaged reporter gene. These results suggest that the major factor for HCR of the MB + VL-treated reporter gene in mammalian cells is DNA repair in the Ad rather than lesion bypass.
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Affiliation(s)
- Derrik M Leach
- Department of Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada
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19
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Rainbow AJ, Zacal NJ, Leach DM. Reduced host cell reactivation of oxidatively damaged DNA in ageing human fibroblasts. Oncol Rep 2013; 29:2493-7. [PMID: 23525587 DOI: 10.3892/or.2013.2358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 02/25/2013] [Indexed: 11/05/2022] Open
Abstract
Many reports have linked oxidative damage to DNA and the associated avoidance and/or repair processes to carcinogenesis, ageing and neurodegeneration. Cancer incidence increases with age and there is evidence that oxidative stress plays a role in human ageing and neurodegeneration. Several reports have suggested that the accumulation of unrepaired DNA lesions plays a causal role in mammalian ageing. Since base excision repair (BER) is the main pathway for the repair of oxidative DNA lesions, the relationship of BER to human ageing and carcinogenesis is of considerable interest. The aim of the present study was to examine the relationship between donor age and increasing time of cells in tissue culture and the repair of oxidative DNA damage in primary human skin fibroblasts. Methylene blue (MB) acts as a photosensitizer and after excitation by visible light (VL) produces reactive oxygen species that result in oxidative damage to DNA. MB+VL produce predominantly 8-hydroxyguanine as well as other single base modifications in DNA that are repaired by BER. We used host cell reactivation (HCR) of a non-replicating recombinant human adenovirus, Ad5CMVlacZ, which expresses the β-galactosidase (β-gal) reporter gene, to measure BER of MB+VL-damaged DNA. HCR of β-gal activity for the MB+VL-treated reporter gene was examined in 10 fibroblast strains from normal donors of ages 2 to 82. The effect of cell passage number on HCR was also examined in human skin fibroblasts from 2 normal donors. We found a significant reduction in HCR with increasing cell passage number, indicating that BER decreases with increasing time of cells grown in tissue culture. We also found a significant correlation of donor age with HCR of the MB+VL-treated reporter gene for high passage number, but not for low passage number fibroblasts. The present study provides evidence that a decrease in BER of oxidatively damaged DNA may play a role in carcinogenesis, ageing and neurodegeneration.
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Affiliation(s)
- Andrew J Rainbow
- Department of Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
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20
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DNA mismatch repair system: repercussions in cellular homeostasis and relationship with aging. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:728430. [PMID: 23213348 PMCID: PMC3504481 DOI: 10.1155/2012/728430] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 09/24/2012] [Accepted: 10/08/2012] [Indexed: 11/18/2022]
Abstract
The mechanisms that concern DNA repair have been studied in the last years due to their consequences in cellular homeostasis. The diverse and damaging stimuli that affect DNA integrity, such as changes in the genetic sequence and modifications in gene expression, can disrupt the steady state of the cell and have serious repercussions to pathways that regulate apoptosis, senescence, and cancer. These altered pathways not only modify cellular and organism longevity, but quality of life (“health-span”). The DNA mismatch repair system (MMR) is highly conserved between species; its role is paramount in the preservation of DNA integrity, placing it as a necessary focal point in the study of pathways that prolong lifespan, aging, and disease. Here, we review different insights concerning the malfunction or absence of the DNA-MMR and its impact on cellular homeostasis. In particular, we will focus on DNA-MMR mechanisms regulated by known repair proteins MSH2, MSH6, PMS2, and MHL1, among others.
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21
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Wang J, Cui Q. Specific Roles of MicroRNAs in Their Interactions with Environmental Factors. J Nucleic Acids 2012; 2012:978384. [PMID: 23209884 PMCID: PMC3502025 DOI: 10.1155/2012/978384] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 09/26/2012] [Indexed: 01/12/2023] Open
Abstract
MicroRNAs (miRNAs) have emerged as critical regulators of gene expression by modulating numerous target mRNAs expression at posttranscriptional level. Extensive studies have shown that miRNAs are critical in various important biological processes, including cell growth, proliferation, differentiation, development, and apoptosis. In terms of their importance, miRNA dysfunction has been associated with a broad range of diseases. Increased number of studies have shown that miRNAs can functionally interact with a wide spectrum of environmental factors (EFs) including drugs, industrial materials, virus and bacterial pathogens, cigarette smoking, alcohol, nutrition, sleep, exercise, stress, and radiation. More importantly, the interactions between miRNAs and EFs have been shown to play critical roles in determining abnormal phenotypes and diseases. In this paper, we propose an outline of the current knowledge about specific roles of miRNAs in their interactions with various EFs and analyze the literatures detailing miRNAs-EFs interactions in the context of various of diseases.
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Affiliation(s)
- Juan Wang
- Department of Biomedical Informatics, Peking University Health Science Center, Beijing 100191, China ; MOE Key Lab of Cardiovascular Sciences, Peking University, Beijing 100191, China ; Institute of Systems Biomedicine, Peking University, Beijing 100191, China
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22
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Jeppesen DK, Bohr VA, Stevnsner T. DNA repair deficiency in neurodegeneration. Prog Neurobiol 2011; 94:166-200. [PMID: 21550379 DOI: 10.1016/j.pneurobio.2011.04.013] [Citation(s) in RCA: 254] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Revised: 04/18/2011] [Accepted: 04/22/2011] [Indexed: 01/17/2023]
Abstract
Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.
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Affiliation(s)
- Dennis Kjølhede Jeppesen
- Danish Centre for Molecular Gerontology and Danish Aging Research Center, University of Aarhus, Department of Molecular Biology, Aarhus, Denmark
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Leach DM, Rainbow AJ. Early host cell reactivation of an oxidatively damaged adenovirus-encoded reporter gene requires the Cockayne syndrome proteins CSA and CSB. Mutagenesis 2011; 26:315-21. [PMID: 21059811 PMCID: PMC3044198 DOI: 10.1093/mutage/geq096] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Revised: 08/22/2010] [Accepted: 09/20/2010] [Indexed: 11/14/2022] Open
Abstract
Reduced host cell reactivation (HCR) of a reporter gene containing 8-oxoguanine (8-oxoG) lesions in Cockayne syndrome (CS) fibroblasts has previously been attributed to increased 8-oxoG-mediated inhibition of transcription resulting from a deficiency in repair. This interpretation has been challenged by a report suggesting reduced expression from an 8-oxoG containing reporter gene occurs in all cells by a mechanism involving gene inactivation by 8-oxoG DNA glycosylase and this inactivation is strongly enhanced in the absence of the CS group B (CSB) protein. The observation of reduced gene expression in the absence of CSB protein led to speculation that decreased HCR in CS cells results from enhanced gene inactivation rather than reduced gene reactivation. Using an adenovirus-based β-galactosidase (β-gal) reporter gene assay, we have examined the effect of methylene blue plus visible light (MB + VL)-induced 8-oxoG lesions on the time course of gene expression in normal and CSA and CSB mutant human SV40-transformed fibroblasts, repair proficient and CSB mutant Chinese hamster ovary (CHO) cells and normal mouse embryo fibroblasts. We demonstrate that MB + VL treatment of the reporter leads to reduced expression of the damaged β-gal reporter relative to control at early time points following infection in all cells, consistent with in vivo inhibition of RNA polII-mediated transcription. In addition, we have demonstrated HCR of reporter gene expression occurs in all cell types examined. A significant reduction in the rate of gene reactivation in human SV40-transformed cells lacking functional CSA or CSB compared to normal cells was found. Similarly, a significant reduction in the rate of reactivation in CHO cells lacking functional CSB (CHO-UV61) was observed compared to the wild-type parental counterpart (CHO-AA8). The data presented demonstrate that expression of an oxidatively damaged reporter gene is reactivated over time and that CSA and CSB are required for normal reactivation.
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Affiliation(s)
| | - Andrew J. Rainbow
- Department of Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada
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24
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Passos-Silva DG, Rajão MA, Nascimento de Aguiar PH, Vieira-da-Rocha JP, Machado CR, Furtado C. Overview of DNA Repair in Trypanosoma cruzi, Trypanosoma brucei, and Leishmania major. J Nucleic Acids 2010; 2010:840768. [PMID: 20976268 PMCID: PMC2952945 DOI: 10.4061/2010/840768] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Revised: 07/29/2010] [Accepted: 08/25/2010] [Indexed: 12/18/2022] Open
Abstract
A wide variety of DNA lesions arise due to environmental agents, normal cellular metabolism, or intrinsic weaknesses in the chemical bonds of DNA. Diverse cellular mechanisms have evolved to maintain genome stability, including mechanisms to repair damaged DNA, to avoid the incorporation of modified nucleotides, and to tolerate lesions (translesion synthesis). Studies of the mechanisms related to DNA metabolism in trypanosomatids have been very limited. Together with recent experimental studies, the genome sequencing of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major, three related pathogens with different life cycles and disease pathology, has revealed interesting features of the DNA repair mechanism in these protozoan parasites, which will be reviewed here.
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Affiliation(s)
- Danielle Gomes Passos-Silva
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil
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25
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Svobodová A, Vostálová J. Solar radiation induced skin damage: review of protective and preventive options. Int J Radiat Biol 2010; 86:999-1030. [PMID: 20807180 DOI: 10.3109/09553002.2010.501842] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Solar energy has a number of short- and long-term detrimental effects on skin that can result in several skin disorders. The aim of this review is to summarise current knowledge on endogenous systems within the skin for protection from solar radiation and present research findings to date, on the exogenous options for such skin photoprotection. RESULTS Endogenous systems for protection from solar radiation include melanin synthesis, epidermal thickening and an antioxidant network. Existing lesions are eliminated via repair mechanisms. Cells with irreparable damage undergo apoptosis. Excessive and chronic sun exposure however can overwhelm these mechanisms leading to photoaging and the development of cutaneous malignancies. Therefore exogenous means are a necessity. Exogenous protection includes sun avoidance, use of photoprotective clothing and sufficient application of broad-spectrum sunscreens as presently the best way to protect the skin. However other strategies that may enhance currently used means of protection are being investigated. These are often based on the endogenous protective response to solar light such as compounds that stimulate pigmentation, antioxidant enzymes, DNA repair enzymes, non-enzymatic antioxidants. CONCLUSION More research is needed to confirm the effectiveness of new alternatives to photoprotection such as use of DNA repair and antioxidant enzymes and plant polyphenols and to find an efficient way for their delivery to the skin. New approaches to the prevention of skin damage are important especially for specific groups of people such as (young) children, photosensitive people and patients on immunosuppressive therapy. Changes in public awareness on the subject too must be made.
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Affiliation(s)
- Alena Svobodová
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc, Czech Republic.
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Ridley AJ, Whiteside JR, McMillan TJ, Allinson SL. Cellular and sub-cellular responses to UVA in relation to carcinogenesis. Int J Radiat Biol 2009; 85:177-95. [PMID: 19296341 DOI: 10.1080/09553000902740150] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
PURPOSE UVA radiation (315-400 nm) contributes to skin aging and carcinogenesis. The aim of this review is to consider the mechanisms that underlie UVA-induced cellular damage, how this damage may be prevented or repaired and the signal transduction processes that are elicited in response to it. RESULTS Exposure to ultraviolet (UV) light is well-established as the causative factor in skin cancer. Until recently, most work on the mechanisms that underlie skin carcinogenesis focused on shorter wavelength UVB radiation (280-315 nm), however in recent years there has been increased interest in the contribution made by UVA. UVA is able to cause a range of damage to cellular biomolecules including lipid peroxidation, oxidized protein and DNA damage, such as 8-oxoguanine and cyclobutane pyrimidine dimers. Such damage is strongly implicated in both cell death and malignant transformation and cells have a number of mechanisms in place to mitigate the effects of UVA exposure, including antioxidants, DNA repair, and stress signalling pathways. CONCLUSIONS The past decade has seen a surge of interest in the biological effects of UVA exposure as its significance to the process of photo-carcinogenesis has become increasingly evident. However, unpicking the unique complexity of the cellular response to UVA, which is only now becoming apparent, will be a major challenge for the field of photobiology in the 21st century.
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Affiliation(s)
- Andrew J Ridley
- Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, UK.
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27
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Kassam SN, Rainbow AJ. UV-inducible base excision repair of oxidative damaged DNA in human cells. Mutagenesis 2008; 24:75-83. [DOI: 10.1093/mutage/gen054] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Rainbow AJ, Zacal NJ. Expression of an adenovirus encoded reporter gene and its reactivation following UVC and oxidative damage in cultured fish cells. Int J Radiat Biol 2008; 84:455-66. [PMID: 18470745 DOI: 10.1080/09553000802078370] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE Recombinant human adenovirus, AdCA35lacZ, was used to examine expression of a reporter gene and its reactivation following UVC (200-280 nm) and oxidative damage in fish cells. MATERIALS AND METHODS AdCA35lacZ is a recombinant nonreplicating human adenovirus, which expresses the beta-galactosidase (beta-gal) reporter gene. UVC light produces DNA damage repaired by nucleotide excision repair (NER). In contrast, methylene blue plus visible light (MB+VL) produces oxidative DNA damage, mainly 8-oxoguanine, that is repaired by base excision repair (BER). We examined expression of the reporter gene and host cell reactivation (HCR) of the UVC-treated and MB+VL-treated reporter gene in fish cells. RESULTS AdCA35lacZ infection of Chinook salmon cells (CHSE-214), eel cells (PBLE) and four rainbow trout cell lines (RTG-2, RT-Gill, RTS-34st and RTS-pBk), but not zebrafish (ZEB) or carp (EPC) cells resulted in expression of beta-gal. HCR of UVC-treated AdCA35lacZ in fish cells varied from that obtained in NER-deficient xeroderma pigmentosum group A fibroblasts to greater than that for NER-proficient normal human fibroblasts. HCR of UVC-treated AdCA35lacZ correlated with beta-gal expression levels for untreated AdCA35lacZ. Exposure of cells to fluorescent light (400-700 nm) increased expression of the undamaged reporter gene in normal human fibroblasts and in all fish cells except PBLE and increased HCR of the UVC-damaged reporter gene in fish cells but not in human fibroblasts. HCR of the MB + VL-treated reporter gene was similar to that in human cells for PBLE, CHSE-214, RTG-2 and RTS-pBk, but was reduced in RT-Gill and RTS-34st cells. CONCLUSIONS These results indicate the detection of functional photoreactivation (PR) of UVC-induced DNA damage in fish cells but not in normal human fibroblasts and a link between NER and transcription of the reporter gene in the fish cells in the absence of PR. We show also efficient BER of the reporter gene in several fish cell lines.
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Affiliation(s)
- Andrew J Rainbow
- Department of Biology, McMaster University, Hamilton, Ontario, Canada.
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Paz-Elizur T, Sevilya Z, Leitner-Dagan Y, Elinger D, Roisman LC, Livneh Z. DNA repair of oxidative DNA damage in human carcinogenesis: potential application for cancer risk assessment and prevention. Cancer Lett 2008; 266:60-72. [PMID: 18374480 DOI: 10.1016/j.canlet.2008.02.032] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Revised: 01/31/2008] [Accepted: 02/11/2008] [Indexed: 12/19/2022]
Abstract
Efficient DNA repair mechanisms comprise a critical component in the protection against human cancer, as indicated by the high predisposition to cancer of individuals with germ-line mutations in DNA repair genes. This includes biallelic germ-line mutations in the MUTYH gene, encoding a DNA glycosylase that is involved in the repair of oxidative DNA damage, which strongly predispose humans to a rare hereditary form of colorectal cancer. Extensive research efforts including biochemical, enzymological and genetic studies in model organisms established that the oxidative DNA lesion 8-oxoguanine is mutagenic, and that several DNA repair mechanisms operate to prevent its potentially mutagenic and carcinogenic outcome. Epidemiological studies on the association with sporadic cancers of single nucleotide polymorphisms in genes such as OGG1, involved in the repair of 8-oxoguanine yielded conflicting results, and suggest a minor effect at best. A new approach based on the functional analysis of DNA repair enzymatic activity showed that reduced activity of 8-oxoguanine DNA glycosylase (OGG) is a risk factor in lung and head and neck cancer. Moreover, the combination of smoking and low OGG activity was associated with a higher risk, suggesting a potential strategy for risk assessment and prevention of lung cancer, as well as other types of cancer.
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Affiliation(s)
- Tamar Paz-Elizur
- Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
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Ghodgaonkar MM, Zacal N, Kassam S, Rainbow AJ, Shah GM. Depletion of poly(ADP-ribose) polymerase-1 reduces host cell reactivation of a UV-damaged adenovirus-encoded reporter gene in human dermal fibroblasts. DNA Repair (Amst) 2008; 7:617-32. [PMID: 18289944 DOI: 10.1016/j.dnarep.2008.01.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2007] [Revised: 01/04/2008] [Accepted: 01/05/2008] [Indexed: 12/19/2022]
Abstract
In response to ultraviolet radiation (UV), mammalian cells rapidly activate a nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP), and we recently showed that one of the causes for PARP-activation is UV-induced direct DNA photolesions which are repaired by nucleotide excision repair process (NER). To determine whether PARP can play a role in NER, we stably depleted PARP in NER-proficient human skin fibroblasts GM637 by DNA vector-based RNAi. In these cells, we examined host cell reactivation (HCR) of UVB or UVC-irradiated recombinant adenovirus AdCA35lacZ, encoding a beta-galactosidase (beta-gal) reporter gene. The depletion of PARP decreased the HCR of UVB- or UVC-damaged reporter gene to a similar extent, indicating the role of PARP in NER. Moreover, PARP-depletion reduced the HCR capacity of the NER-competent GM637 cells to a level closer to that in the XP-C and CS-B cell lines, which are deficient in the lesion recognition steps of the global genome repair (GGR) and transcription-coupled repair (TCR) sub-pathways of NER, respectively. In order to identify the potential role of PARP in these two sub-pathways of NER from that of its known role in base excision repair (BER) of UVB-induced oxidant damage, we depleted PARP from XP-C and CS-B cells and examined HCR of the reporter gene damaged by UVB, UVC or photoactivated methylene blue, the latter causing predominantly 8-oxo-2'-deoxyguanosine damage that is repaired by BER. Interestingly, a decreased HCR due to PARP-depletion was observed in both the NER-deficient cell lines in response to virus damaged by these three agents, albeit with different kinetics from 12 to 44h after infection. The role of PARP in NER was highlighted by a decreased clonogenic survival of UV-irradiated NER-competent GM637 cells depleted of PARP. Our results, while confirming the role of PARP in base excision repair, suggest a novel role of PARP in both the GGR and TCR sub-pathways of NER.
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Affiliation(s)
- Medini M Ghodgaonkar
- Laboratory for Skin Cancer Research, CHUL Research Centre (CHUQ), Faculty of Medicine, Laval University, Quebec, Quebec G1V 4G2, Canada
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Machado-Silva A, Teixeira SMR, Franco GR, Macedo AM, Pena SDJ, McCulloch R, Machado CR. Mismatch repair in Trypanosoma brucei: heterologous expression of MSH2 from Trypanosoma cruzi provides new insights into the response to oxidative damage. Gene 2008; 411:19-26. [PMID: 18262734 DOI: 10.1016/j.gene.2007.12.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2007] [Revised: 12/14/2007] [Accepted: 12/17/2007] [Indexed: 01/06/2023]
Abstract
Trypanosomes are unicellular eukaryotes that cause disease in humans and other mammals. Trypanosoma cruzi and Trypanosoma brucei are the causative agents, respectively, of Chagas disease in the Americas and sleeping sickness in sub-Saharan Africa. To better comprehend the interaction of these parasites with their hosts, understanding the mechanisms involved in the generation of genetic variability is critical. One such mechanism is mismatch repair (MMR), which has a crucial, evolutionarily conserved role in maintaining the fidelity of DNA replication, as well as acting in other cellular processes, such as DNA recombination. Here we have attempted to complement T. brucei MMR through the expression of MSH2 from T. cruzi. Our results show that T. brucei MSH2-null mutants are more sensitive to hydrogen peroxide (H2O2) than wild type cells, suggesting the involvement of MSH2 in the response to oxidative stress in this parasite. This phenotype is reverted by the expression of either the T. cruzi or the T. brucei MSH2 protein in the MSH2-null mutants. In contrast, MMR complementation, as assessed by resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and microsatellite instability, was not achieved by the heterologous expression of T. cruzi MSH2. This finding, associated to the demonstration that mutation of MLH1, another component of the MMR system, did not affect sensitivity of T. brucei cells to H2O2, suggests an additional role of MSH2 in dealing with oxidative damage in these parasites, which may occur independently of MMR.
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Affiliation(s)
- Alice Machado-Silva
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Departamento de Bioquímica e Imunologia, Belo Horizonte, Brazil
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Kassam SN, Rainbow AJ. Deficient base excision repair of oxidative DNA damage induced by methylene blue plus visible light in xeroderma pigmentosum group C fibroblasts. Biochem Biophys Res Commun 2007; 359:1004-9. [PMID: 17573042 DOI: 10.1016/j.bbrc.2007.06.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2007] [Accepted: 06/01/2007] [Indexed: 11/25/2022]
Abstract
Methylene blue plus visible light (MB+VL) results in oxidative DNA damage, producing predominantly 7,8-dihydroxy-8-oxoguanine and other single base modifications that are repaired by base excision repair (BER). AdCA17 is non-replicating recombinant human adenovirus that infects human cells and expresses the beta-galactosidase (beta-gal) reporter gene. We have examined host cell reactivation (HCR) of beta-gal activity for (MB+VL)-treated AdCA17 in cells from patients with xeoroderma pigmentosum from complementation group C (XP-C). HCR was substantially reduced in an SV40 transformed XP-C fibroblast compared to two SV40-transformed normal cells and in three XP-C primary fibroblast strains compared to four normal strains for both untreated and UVC-treated cells. These results indicate an involvement of the XPC gene in BER of MB+VL-induced oxidative DNA damage. In addition, pre-UVC-treatment of both normal and XP-C fibroblasts resulted in enhanced HCR of the MB+VL-treated reporter gene giving evidence for a UVC-inducible and XPC-independent BER pathway in human cells.
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Affiliation(s)
- Shaqil N Kassam
- Department of Biology, McMaster University, Hamilton, Ont., Canada L8S 4K1
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