DNA Repair最新文献

{"title":"An exchange of single amino acid between the phosphohydrolase modules of Escherichia coli MutT and Mycobacterium smegmatis MutT1 switches their cleavage specificities","authors":"Elhassan Ali Fathi Emam ,&nbsp;Koyel Roy ,&nbsp;Umesh Varshney","doi":"10.1016/j.dnarep.2024.103693","DOIUrl":"10.1016/j.dnarep.2024.103693","url":null,"abstract":"<div><p>MutT proteins belong to the Nudix hydrolase superfamily that includes a diverse group of Mg²⁺ requiring enzymes. These proteins use a generalized substrate, <strong>nu</strong>cleoside <strong>di</strong>phosphate linked to a chemical group <strong>X (NDP-X</strong>), to produce nucleoside monophosphate (NMP) and the moiety X linked with phosphate (XP). <em>E. coli</em> MutT (<em>Eco</em>MutT) and mycobacterial MutT1 (<em>Msm</em>MutT1) belong to the Nudix hydrolase superfamily that utilize 8-oxo-(d)GTP (referring to both 8-oxo-GTP or 8-oxo-dGTP). However, predominant products of their activities are different. While <em>Eco</em>MutT produces 8-oxo-(d)GMP, <em>Msm</em>MutT1 gives rise to 8-oxo-(d)GDP. Here, we show that the altered cleavage specificities of the two proteins are largely a consequence of the variation at the equivalent of Gly37 (G37) in <em>Eco</em>MutT to Lys (K65) in the <em>Msm</em>MutT1. Remarkably, mutations of G37K (<em>Eco</em>MutT) and K65G (<em>Msm</em>MutT1) switch their cleavage specificities to produce 8-oxo-(d)GDP, and 8-oxo-(d)GMP, respectively. Further, a time course analysis using 8-oxo-GTP suggests that <em>Msm</em>MutT1(K65G) hydrolyses 8-oxo-(d)GTP to 8-oxo-(d)GMP in a two-step reaction via 8-oxo-(d)GDP intermediate. Expectedly, unlike <em>Eco</em>MutT (G37K) and <em>Msm</em>MutT1, <em>Eco</em>MutT and <em>Msm</em>MutT1 (K65G) rescue an <em>E. coli ΔmutT</em> strain, better by decreasing A to C mutations.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103693"},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141049690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of rRNA in maintaining genome stability","authors":"Peng Li ,&nbsp;Xiaochun Yu","doi":"10.1016/j.dnarep.2024.103692","DOIUrl":"10.1016/j.dnarep.2024.103692","url":null,"abstract":"<div><p>Over the past few decades, unbiased approaches such as genetic screening and protein affinity purification have unveiled numerous proteins involved in DNA double-strand break (DSB) repair and maintaining genome stability. However, despite our knowledge of these protein factors, the underlying molecular mechanisms governing key cellular events during DSB repair remain elusive. Recent evidence has shed light on the role of non-protein factors, such as RNA, in several pivotal steps of DSB repair. In this review, we provide a comprehensive summary of these recent findings, highlighting the significance of ribosomal RNA (rRNA) as a critical mediator of DNA damage response, meiosis, and mitosis. Moreover, we discuss potential mechanisms through which rRNA may influence genome integrity.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103692"},"PeriodicalIF":3.8,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000685/pdfft?md5=cf14878fb4dbf102d1edc94574f1ef8e&pid=1-s2.0-S1568786424000685-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141054916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cdc48/p97 segregase: Spotlight on DNA-protein crosslinks","authors":"Audrey Noireterre,&nbsp;Françoise Stutz","doi":"10.1016/j.dnarep.2024.103691","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103691","url":null,"abstract":"<div><p>The ATP-dependent molecular chaperone Cdc48 (in yeast) and its human counterpart p97 (also known as VCP), are essential for a variety of cellular processes, including the removal of DNA-protein crosslinks (DPCs) from the DNA. Growing evidence demonstrates in the last years that Cdc48/p97 is pivotal in targeting ubiquitinated and SUMOylated substrates on chromatin, thereby supporting the DNA damage response. Along with its cofactors, notably Ufd1-Npl4, Cdc48/p97 has emerged as a central player in the unfolding and processing of DPCs. This review introduces the detailed structure, mechanism and cellular functions of Cdc48/p97 with an emphasis on the current knowledge of DNA-protein crosslink repair pathways across several organisms. The review concludes by discussing the potential therapeutic relevance of targeting p97 in DPC repair.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103691"},"PeriodicalIF":3.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000673/pdfft?md5=c07c88cef240c56325edcd424bfa1510&pid=1-s2.0-S1568786424000673-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140918281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA-PK inhibitor AZD7648 is a more portent radiosensitizer than PARP inhibitor Olaparib in BRCA1/2 deficient tumors","authors":"Taixiang Wang,&nbsp;Alastair H. Kyle,&nbsp;Jennifer H.E. Baker,&nbsp;Nannan A. Liu,&nbsp;Judit P. Banáth,&nbsp;Sevin Teymori,&nbsp;Andrew I. Minchinton","doi":"10.1016/j.dnarep.2024.103689","DOIUrl":"10.1016/j.dnarep.2024.103689","url":null,"abstract":"<div><p>The effectiveness of radiotherapy depends on the sensitivities of ‘normal’ and cancer cells to the administered radiation dose. Increasing the radiosensitivity of cancers by inhibiting DNA damage repair is a goal of much current research, however success depends on avoiding concomitant sensitization of normal tissues inevitably irradiated during therapy. In this study we investigated the mechanisms of radiosensitization for DNA-PK and PARP inhibitors by examining the impacts on proliferating vs quiescent cell populations. Experiments were performed in <em>BRCA1/2</em>^null and wild-type parental cancer models <em>in vitro</em> and <em>in vivo</em>. Overall AZD7648 has greater radiosensitizing activity relative to Olaparib, with BRCA2-deficient models showing the greatest sensitivity. However, DNA-PK inhibitor AZD7648 also produced greater toxicity in all irradiated mice. While both DNA-PK and PARP inhibition sensitizes wild type tumor cells to radiation, in BRCA1/2 deficient cells PARP inhibition by Olaparib had limited radiosensitization capacity. Quiescent cells are more radioresistant than proliferating cells, and these were also effectively sensitized by AZD7648 while Olaparib was unable to increase radiation-induced cell kill, even in <em>BRCA1/2</em>^null cells. These findings underscore the distinct mechanisms of radiosensitization for DNA-PK and PARP inhibitors. While DNA-PK inhibitors are able to target both proliferating and non-proliferating tumor cells for greater overall anti-cancer benefit, their application is limited by exacerbation of normal tissue toxicities. Conversely, PARP inhibitors exhibit selective activity for proliferating cells, providing a mechanism for targeting activity to cancers, but due to poor activity in non-proliferating cells they have an overall reduced impact on tumor growth control. This study highlights the importance of creating a therapeutic ratio with DNA damage repair inhibition radiation sensitizing strategies.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103689"},"PeriodicalIF":3.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pold4 subunit of replicative polymerase δ promotes fork slowing at broken templates","authors":"Kota Kojima ,&nbsp;Hiromori Ohkubo ,&nbsp;Ryotaro Kawasumi ,&nbsp;Kouji Hirota","doi":"10.1016/j.dnarep.2024.103688","DOIUrl":"10.1016/j.dnarep.2024.103688","url":null,"abstract":"<div><p>Single-strand breaks (SSBs) are the most frequent type of lesion, and replication across such lesions leads to double-strand breaks (DSBs). DSBs that arise during replication are repaired by homologous recombination (HR) and are suppressed by fork reversal. Poly[ADP-ribose] polymerase I (PARP1) and the proofreading exonuclease activity of replicative polymerase ε (Polε) are required for fork reversal when leading strand replication encounters SSBs. However, the mechanism underlying fork reversal at the SSB during lagging-strand replication remains elusive. We here demonstrate that the Pold4 subunit of replicative polymerase δ (Polδ) plays a role in promoting fork reversal during lagging strand replication on a broken template. <em>POLD4</em>^<em>-/-</em> cells exhibited heightened sensitivity to camptothecin (CPT) but not to other DNA-damaging agents compared to wild-type cells. This selective CPT sensitivity in <em>POLD4</em>^<em>-/-</em> cells suggests that Pold4 suppresses DSBs during replication, as CPT induces significant SSBs during replication, which subsequently lead to DSBs. To explore the functional interactions among Pold4, Polε exonuclease, and PARP1 in DSB suppression, we generated <em>PARP1</em>^<em>-/-</em>, <em>POLD4</em>^<em>-/-</em>, Polε exonuclease-deficient <em>POLE1</em>^{<em>exo-/-</em>}, <em>PARP1</em>^<em>-/-</em><em>/POLD4</em>^<em>-/-</em>, and <em>POLD4</em>^<em>-/-</em><em>/POLE1</em>^{<em>exo-/-</em>} cells. These epistasis analyses showed that Pold4 is involved in the PARP1-Polε exonuclease-mediated fork reversal following CPT treatment. These results suggest that Pold4 aids in fork reversal when lagging strand replication stalls on a broken template. In conclusion, the Pold4 subunit of Polδ has roles in the PARP1-Polε exonuclease-mediated fork reversal, contributing to the suppression of DSBs.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103688"},"PeriodicalIF":3.8,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140763790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NEIL3: A unique DNA glycosylase involved in interstrand DNA crosslink repair","authors":"Leah E. Oswalt ,&nbsp;Brandt F. Eichman","doi":"10.1016/j.dnarep.2024.103680","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103680","url":null,"abstract":"<div><p>Endonuclease VIII-like 3 (NEIL3) is a versatile DNA glycosylase that repairs a diverse array of chemical modifications to DNA. Unlike other glycosylases, NEIL3 has a preference for lesions within single-strand DNA and at single/double-strand DNA junctions. Beyond its canonical role in base excision repair of oxidized DNA, NEIL3 initiates replication-dependent interstrand DNA crosslink repair as an alternative to the Fanconi Anemia pathway. This review outlines our current understanding of NEIL3’s biological functions, role in disease, and three-dimensional structure as it pertains to substrate specificity and catalytic mechanism.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103680"},"PeriodicalIF":3.8,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000569/pdfft?md5=f79831f8a25151a8efdb4bb77e08b28f&pid=1-s2.0-S1568786424000569-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140646716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA repair deficiencies and neurodegeneration","authors":"Baptiste Ropert ,&nbsp;Christian Gallrein ,&nbsp;Björn Schumacher","doi":"10.1016/j.dnarep.2024.103679","DOIUrl":"10.1016/j.dnarep.2024.103679","url":null,"abstract":"<div><p>Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer’s Disease is the most widespread and also most acknowledged form of dementia today. Together with Parkinson’s Disease they account for over 90 % cases of neurodegenerative disorders caused by proteopathies. Far less known are the neurodegenerative pathologies in DNA repair deficiency syndromes. Such diseases like Cockayne - or Werner Syndrome are described as progeroid syndromes – diseases that cause the premature ageing of the affected persons, and there are clear implications of such diseases in neurologic dysfunction and degeneration. In this review, we aim to draw the attention on commonalities between proteopathy-associated neurodegeneration and neurodegeneration caused by DNA repair defects and discuss how mitochondria are implicated in the development of both disorder classes. Furthermore, we highlight how nematodes are a valuable and indispensable model organism to study conserved neurodegenerative processes in a fast-forward manner.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"138 ","pages":"Article 103679"},"PeriodicalIF":3.8,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000557/pdfft?md5=3327f387b995932786f0abdcf14eb3ac&pid=1-s2.0-S1568786424000557-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140610184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic stress and impaired DNA repair in Alzheimer disease","authors":"Jolien Neven ,&nbsp;Luidy Kazuo Issayama,&nbsp;Ilse Dewachter,&nbsp;David M. Wilson III","doi":"10.1016/j.dnarep.2024.103678","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103678","url":null,"abstract":"<div><p>Alzheimer disease (AD) is the most prominent form of dementia and has received considerable attention due to its growing burden on economic, healthcare and basic societal infrastructures. The two major neuropathological hallmarks of AD, i.e., extracellular amyloid beta (Aβ) peptide plaques and intracellular hyperphosphorylated Tau neurofibrillary tangles, have been the focus of much research, with an eye on understanding underlying disease mechanisms and identifying novel therapeutic avenues. One often overlooked aspect of AD is how Aβ and Tau may, through indirect and direct mechanisms, affect genome integrity. Herein, we review evidence that Aβ and Tau abnormalities induce excessive genomic stress and impair genome maintenance mechanisms, events that can promote DNA damage-induced neuronal cell loss and associated brain atrophy.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103678"},"PeriodicalIF":3.8,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140647235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CometChip enables parallel analysis of multiple DNA repair activities [DNA repair 106 (2021) 103176–103202]","authors":"Jing Ge ,&nbsp;Le P. Ngo ,&nbsp;Simran Kaushal ,&nbsp;Ian J. Tay ,&nbsp;Elina Thadhani ,&nbsp;Jennifer E. Kay ,&nbsp;Patrizia Mazzucato ,&nbsp;Danielle Chow ,&nbsp;Jessica Fessler ,&nbsp;David M. Weingeist ,&nbsp;Robert W. Sobol ,&nbsp;Leona D. Samson ,&nbsp;Scott R. Floyd ,&nbsp;Bevin P. Engelward","doi":"10.1016/j.dnarep.2024.103677","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103677","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"138 ","pages":"Article 103677"},"PeriodicalIF":3.8,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000533/pdfft?md5=e2c7d94a15fc06bbaf21f2ae108998fa&pid=1-s2.0-S1568786424000533-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140350226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMC-5/6 complex subunit NSE-1 plays a crucial role in meiosis and DNA repair in Caenorhabditis elegans","authors":"Arome Solomon Odiba ,&nbsp;Chiemekam Samuel Ezechukwu ,&nbsp;Guiyan Liao ,&nbsp;Ye Hong ,&nbsp;Wenxia Fang ,&nbsp;Cheng Jin ,&nbsp;Anton Gartner ,&nbsp;Bin Wang","doi":"10.1016/j.dnarep.2024.103669","DOIUrl":"10.1016/j.dnarep.2024.103669","url":null,"abstract":"<div><p>The SMC5/6 complex is evolutionarily conserved across all eukaryotes and plays a pivotal role in preserving genomic stability. Mutations in genes encoding SMC5/6 complex subunits have been associated with human lung disease, immunodeficiency, and chromosome breakage syndrome. Despite its critical importance, much about the SMC5/6 complex remains to be elucidated. Various evidences have suggested possible role of a subunit of the SMC5/6 complex, NSE1, in chromosome segregation and DNA repair. Current knowledge regarding the role of NSE1 is primarily derived from single-cell-based analyses in yeasts, <em>Arabidopsis thaliana</em>, and human cell lines. However, our understanding of its function is still limited and requires further investigation. This study delves into the role of <em>nse-1</em> in <em>Caenorhabditis elegans</em>, revealing its involvement in meiotic recombination and DNA repair. <em>nse-1</em> mutants display reduced fertility, increased male incidence, and increased sensitivity to genotoxic chemicals due to defects in meiotic chromosome segregation and DNA repair. These defects manifest as increased accumulation of RAD-51 foci, increased chromosome fragmentation, and susceptibility to MMS, cisplatin, and HU. Furthermore, <em>nse-1</em> mutation exacerbates germ cell death by upregulating <em>ced-13</em> and <em>egl-1</em> genes involved in the CEP-1/p53-mediated apoptotic pathway. NSE-1 is essential for the proper localization of NSE-4 and MAGE-1 on the chromosomes. Collectively, these findings firmly establish <em>nse-1</em> as a crucial factor in maintaining genomic stability.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"137 ","pages":"Article 103669"},"PeriodicalIF":3.8,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140148325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}