DNA Repair最新文献

{"title":"Obituary: Francis Fabre (1940–2024)","authors":"Eric Coïc","doi":"10.1016/j.dnarep.2025.103838","DOIUrl":"10.1016/j.dnarep.2025.103838","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103838"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906162","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 differential roles of rad9 alternatively spliced forms in double- strand DNA break repair during Drosophila meiosis","authors":"Bareket Goldstein,&nbsp;Suad Sheikh-Suliman,&nbsp;Anna Bakhrat,&nbsp;Uri Abdu","doi":"10.1016/j.dnarep.2025.103833","DOIUrl":"10.1016/j.dnarep.2025.103833","url":null,"abstract":"<div><div>The 9–1–1 complex, comprising the Rad9, Hus1 and Rad1 proteins, is believed to operate as a component of a DNA damage checkpoint pathway. Our initial analysis of the <em>Drosophila hus1</em> gene showed that Hus1 plays a dual role in meiosis, regulating both meiotic DNA damage checkpoint and homologous recombination repair. In this study, we further analyzed the meiotic roles of another protein in the complex, Rad9, which has two alternatively spliced forms, Rad9A and Rad9B. Using CRISPR/Cas9, we generated flies mutant for both <em>rad9</em> isoforms. We found that, similarly to <em>hus1</em>, mutations in <em>rad9</em> lead to female sterility. Also, double-strand DNA breaks (DSBs) that form during meiosis are not processed efficiently, and the DNA within the oocyte nucleus fails to form its characteristic shape in <em>rad9</em> mutants. On the other hand, the <em>hus1</em> mutation completely disrupts checkpoint activation in DSB repair enzyme mutants, whereas the <em>rad9</em> mutation only partially impairs checkpoint activation in this context. Moreover, spatial rescue experiments revealed that Rad9B is efficient in repairing meiotic DSBs, while Rad9A is not. Furthermore, we found that female fertility in <em>rad9</em> mutants depends on early efficient meiotic DSB repair but not on karyosome formation. In summary, our results demonstrate a differential role of Rad9 alternatively spliced forms during <em>Drosophila</em> meiosis in oogenesis, and while former studies showed that Hus1 is sufficient for the effective activation of the meiotic recombination checkpoint, our results revealed that this is not true for Rad9.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103833"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838009","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":"Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer","authors":"Suisui Hao ,&nbsp;Zhaojin Liu ,&nbsp;Heinz-Josef Lenz ,&nbsp;Jian Yu ,&nbsp;Lin Zhang","doi":"10.1016/j.dnarep.2025.103831","DOIUrl":"10.1016/j.dnarep.2025.103831","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the United States. A key driver of CRC development is microsatellite instability (MSI), which is caused by DNA mismatch repair deficiency and characterized by hypermutability of short-tandem repeat sequences. A significant portion of MSI CRCs do not respond to checkpoint immunotherapy treatments, highlighting an unmet need for improved therapies. Recent studies have revealed that MSI cancer cells require Werner (WRN), a RecQ family DNA helicase, for survival. Inhibiting WRN has emerged as a promising approach for targeting MSI CRCs that are insensitive to standard therapies. Several highly potent small-molecule WRN inhibitors have been developed and exhibited striking <em>in vitro</em> and <em>in vivo</em> activities against MSI cancers. Two of these WRN inhibitors, HRO761 and VVD-133214, have recently entered clinical trials. In this review, we summarize recent studies on WRN as a synthetic lethal target in MSI CRC and the development of WRN inhibitors as a new class of anticancer agents.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103831"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799196","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":"Role of HSP40 proteins in genome maintenance, insulin signaling and cancer therapy","authors":"Yaping Huang ,&nbsp;Guo-Min Li","doi":"10.1016/j.dnarep.2025.103839","DOIUrl":"10.1016/j.dnarep.2025.103839","url":null,"abstract":"<div><div>The DnaJ heat shock protein family (HSP40) is the biggest chaperone family in mammalian cells, mainly functioning as cochaperone of HSP70 to maintain proteostasis and cellular homeostasis under both normal and stressful conditions. Although the functions of HSP70s have been extensively studied in diverse biological pathways and senesces including genome maintenance, HSP40s’ biological functions at basal state or in response to exogenous insults remain largely under-investigated. Emerging evidence shows that HSP40 proteins participate in genome maintenance pathways and modulate cancer therapy efficacy. This review aims to summarize recent progresses regarding HSP40’s functions in genome maintenance and cancer therapy, and provides hints for future studies in the field.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103839"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855996","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":"Role of NEIL1 in genome maintenance","authors":"Amanda K. McCullough ,&nbsp;Irina G. Minko ,&nbsp;Michael M. Luzadder ,&nbsp;Jamie T. Zuckerman ,&nbsp;Vladimir L. Vartanian ,&nbsp;Pawel Jaruga ,&nbsp;Miral Dizdaroglu ,&nbsp;R. Stephen Lloyd","doi":"10.1016/j.dnarep.2025.103820","DOIUrl":"10.1016/j.dnarep.2025.103820","url":null,"abstract":"<div><div>Phylogenetic analyses of DNA glycosylases that function in the initiation step of base excision repair reveal a high degree of conservation within the genes encoding Nei-like DNA glycosylase 1 (NEIL1). In concert with other glycosylases, this enzyme is an important player in cleansing both nuclear and mitochondrial genomes of a wide variety of damaged DNA bases. The relative efficiency of NEIL1 to catalyze release of ring-opened formamido-pyrimidines (Fapy) and alkylated-Fapy adducts, multiple ring-saturated pyrimidines, secondary oxidation products of 8-oxoguanine, and psoralen-derived crosslinks is augmented by pre-mRNA editing at codon 242, resulting in cells containing both NEIL1-Lys242 and edited Arg242. The biological significance of NEIL1 was revealed through investigations of mutagenesis and carcinogenesis in murine models, primarily using aflatoxin B₁ (AFB₁) as a genotoxicant challenge, which forms stable AFB₁-FapyGua adducts. Specifically, <em>Neil1</em> knockout mice were &gt; 3-fold more susceptible to AFB₁-induced carcinogenesis as compared to either wild-type or nucleotide excision repair-deficient <em>Xpa</em>^<em>-/-</em> mice. These data are well-supported by duplex sequencing analyses that showed increased AFB₁-induced mutagenesis in <em>Neil1</em>^<em>-/-</em> mice relative to wild-type or <em>Xpa</em>^<em>-/-</em> mice. Given the biological impact of Neil1 deficiencies in cancer, metabolic syndrome, and neurodegeneration, extrapolation to humans carrying single nucleotide polymorphisms (SNPs) in NEIL1 may suggest that deleterious variants could increase disease risk following various genotoxicant exposures. To address this hypothesis, we have undertaken a systematic characterization of human NEIL1 SNP variants that are distributed throughout the world. The goal of this review is to provide comprehensive analyses of the biochemistry and biology of NEIL1.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103820"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487984","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":"Targeting dePARylation in cancer therapy","authors":"Peng Li ,&nbsp;Duo Wu ,&nbsp;Xiaochun Yu","doi":"10.1016/j.dnarep.2025.103824","DOIUrl":"10.1016/j.dnarep.2025.103824","url":null,"abstract":"<div><div>Poly(ADP-ribosyl)ation (PARylation), a reversible post-translational modification mediated by poly(ADP-ribose) polymerases (PARPs), plays crucial roles in DNA replication and DNA damage repair. Since interfering PARylation induces selective cytotoxicity in tumor cells with homologous recombination defects, PARP inhibitors (PARPi) have significant clinical impacts in treating BRCA-mutant cancer patients. Likewise, dePARylation is also essential for optimal DNA damage response and genomic stability. This process is mediated by a group of dePARylation enzymes, such as poly(ADP-ribose) glycohydrolase (PARG). Currently, several novel PARG inhibitors have been developed and examined in preclinical and clinical studies, demonstrating promising anti-cancer activity distinct from PARP inhibitors. This review discusses the role of dePARylation in genome stability and the potential of PARG inhibitors in cancer therapy.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103824"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562640","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 hidden elephant: Modified abasic sites and their consequences","authors":"Anna V. Yudkina ,&nbsp;Dmitry O. Zharkov","doi":"10.1016/j.dnarep.2025.103823","DOIUrl":"10.1016/j.dnarep.2025.103823","url":null,"abstract":"<div><div>Abasic, or apurinic/apyrimidinic sites (AP sites) are among the most abundant DNA lesions, appearing in DNA both through spontaneous base loss and as intermediates of base excision DNA repair. Natural aldehydic AP sites have been known for decades and their interaction with the cellular replication, transcription and repair machinery has been investigated in detail. Oxidized AP sites, produced by free radical attack on intact nucleotides, received much attention recently due to their ability to trap DNA repair enzymes and chromatin structural proteins such as histones. In the past few years, it became clear that the reactive nature of aldehydic and oxidized AP sites produces a variety of modifications, including AP site–protein and AP site–peptide cross-links, adducts with small molecules of metabolic or xenobiotic origin, and AP site-mediated interstrand DNA cross-links. The diverse chemical nature of these common-origin lesions is reflected in the wide range of their biological consequences. In this review, we summarize the data on the mechanisms of modified AP sites generation, their abundance, the ability to block DNA polymerases or cause nucleotide misincorporation, and the pathways of their repair.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103823"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562469","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":"Repair pathway coordination from gap filling by polβ and subsequent nick sealing by LIG1 or LIG3α governs BER efficiency at the downstream steps","authors":"Melike Çağlayan","doi":"10.1016/j.dnarep.2025.103826","DOIUrl":"10.1016/j.dnarep.2025.103826","url":null,"abstract":"<div><div>Base excision repair (BER) is the critical mechanism for preventing mutagenic and lethal consequences of single base lesions generated by endogenous factors or exposure to environmental hazards. BER pathway involves multi-step enzymatic reactions that require a tight coordination between repair proteins to transfer DNA intermediates in an orderly manner. Though often considered an accurate process, the BER can contribute to genome instability if normal coordination between gap filling by DNA polymerase (pol) β and subsequent nick sealing by DNA ligase 1 (LIG1) or DNA ligase 3α (LIG3α) breaks down at the downstream steps. Our studies demonstrated that an inaccurate DNA ligation by LIG1/LIG3α, stemming from an uncoordinated repair with polβ, leads to a range of deviations from canonical BER pathway, faulty repair events, and formation of deleterious DNA intermediates. Furthermore, X-ray repair cross-complementing protein 1 (XRCC1), as a scaffolding factor, enhances the processivity of downstream steps, and the DNA-end processing enzymes, Aprataxin (APTX), Flap-Endonuclease 1 (FEN1), and AP-Endonuclease 1 (APE1), play critical roles for cleaning of ligase failure products and proofreading of polβ errors in coordination with BER ligases. Overall, our studies contribute to understanding of how a multi-protein repair complex interplay at the final steps to maintain the repair efficiency.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103826"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609266","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":"The effect of methylation and hydroxymethylation of cytosine on activity and fidelity of Pol λ and Pol β","authors":"Evgeniy S. Shilkin ,&nbsp;Daria V. Petrova ,&nbsp;Alexander A. Kruchinin ,&nbsp;Dmitry O. Zharkov ,&nbsp;Alena V. Makarova","doi":"10.1016/j.dnarep.2025.103815","DOIUrl":"10.1016/j.dnarep.2025.103815","url":null,"abstract":"<div><div>Сytosine methylation in CpG dinucleotides is the most common epigenetic mark in human cells. Under active demethylation process 5-methylcytosine (mC) can be converted to 5-hydroxymethylcytosine (hmC). Cytosine methylation increases the risk of adjacent nucleotide damage, including the oxidation of guanine. DNA polymerases might encounter mC and hmC during DNA repair or translesion synthesis. Here, we analyze the activity of X-family polymerases Pol β and Pol λ opposite mC and hmC as well as opposite 8-oxoG adjacent to mC in the TCG context. We demonstrate that hmC has no pronounced effect on Pol β and Pol λ activity while cytosine methylation moderately suppresses the efficiency of dGMP incorporation by Pol β but not Pol λ. Pol λ was not affected by + 2 cytosine methylation when synthesizing across 8-oxoG. In contrast, cytosine methylation slightly increased incorporation of dCMP opposite 8-oxoG adjacent to mC but reduced the extension of the 8-oxoG:C pair by Pol β.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"148 ","pages":"Article 103815"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527037","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":"Advances in diagnostic and therapeutic applications of mismatch repair loss in cancer","authors":"JT DeWitt ,&nbsp;D. Jimenez-Tovar ,&nbsp;A. Mazumder ,&nbsp;S. Haricharan","doi":"10.1016/j.dnarep.2025.103822","DOIUrl":"10.1016/j.dnarep.2025.103822","url":null,"abstract":"<div><div>Mismatch repair (MMR) is a highly conserved, fundamental DNA damage repair pathway that maintains genomic fidelity during cell replication. MMR dysregulation contributes to tumor formation by promoting genomic instability thereby increasing the frequency of potentially oncogenic mutational events. Therefore, MMR dysregulation, in its tumor suppressor role, is largely studied in the context of genomic instability and associated response to immune checkpoint blockade therapies. However, a growing body of literature suggests that the impact of MMR dysregulation on tumor phenotypes is more nuanced than a concerted impact on genomic stability. Rather, loss of individual MMR genes promotes distinct cancer-relevant biological phenotypes, and these phenotypes are further modulated by the tissue of tumor origin. Here, we explore relevant literature and review the prognostic and predictive significance of these non-canonical discoveries.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"147 ","pages":"Article 103822"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577420","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}