DNA Repair最新文献

{"title":"CPD photolyase evolution supports amphibian UV-sensitivity hypothesis","authors":"James Eduardo Lago Londero ,&nbsp;Rayana dos Santos Feltrin ,&nbsp;Ana Lucia Anversa Segatto ,&nbsp;André Passaglia Schuch","doi":"10.1016/j.dnarep.2025.103900","DOIUrl":"10.1016/j.dnarep.2025.103900","url":null,"abstract":"<div><div>The UV-sensitivity hypothesis for amphibian decline proposes that interspecific variation in cyclobutane pyrimidine dimer (CPD) photolyase activity determines species’ UV sensitivity, which is linked to their natural history and population trends. Here, to shed light on the molecular basis of UV resistance variation, we investigated the evolutionary dynamics of CPD photolyases in amphibians focusing on regions and sites relevant to protein function. Our evolutionary analyses revealed that amino acids critical for CPD photolyase function are highly conserved and their codons have been evolving under purifying selection. Three tryptophan residues, critical for light-dependent repair and potentially for dark repair, are highly conserved in CPD photolyases across species. Nevertheless, we identified variations in functionally relevant CPD photolyase amino acids across amphibian clades, some of which are predicted to contract the active site and destabilize the protein structure. Caudata CPD photolyases contain functionally relevant variations likely linked to the high UV sensitivity of salamanders and newts. In Gymnophiona, we found relaxed purifying selection in CPD photolyase codons, as well as functionally relevant amino acid variations, likely reflecting the fossorial, dark-dwelling lifestyle of caecilians. Strikingly, most amphibian species with decreasing populations exhibit CPD photolyases with functionally relevant amino acid variations, and this pattern is even stronger for variations that disrupt protein structure. For example, two structurally disruptive, functionally relevant amino acid variations co-occur in CPD photolyases of species from the genera <em>Bombina</em> (Anura) and <em>Ambystoma</em> (Caudata), most of which exhibit declining populations. This study shows that species-specific differences in CPD photolyases underscore the UV-sensitivity hypothesis in amphibian ecology and conservation.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"154 ","pages":"Article 103900"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246107","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 comet assay: A contemporary approach for detecting genomic instability","authors":"Xingkai He ,&nbsp;Feng Chen ,&nbsp;Linmin Zhou ,&nbsp;Yuanqing Sun ,&nbsp;Qi Liu ,&nbsp;Weicheng Chen ,&nbsp;Luyao Zhu ,&nbsp;Jun Zhang ,&nbsp;Wei-Guo Zhu","doi":"10.1016/j.dnarep.2025.103899","DOIUrl":"10.1016/j.dnarep.2025.103899","url":null,"abstract":"<div><div>The comet assay has evolved into a high-resolution, multifunctional technique for evaluating DNA damage, repair capacity, and epigenetic modifications. Over the past fifteen years, significant advancements-including the enzyme-modified comet assays (EMCA), Comet-FISH, and high-throughput platforms have substantially expanded its analytical capabilities. Specialized formats like the Flash comet assay and the BrdU comet assay further enhance the discrimination of DNA strand break types and replication-associated damage. Despite these innovations, issues related to standardization, reproducibility, and inter-laboratory consistency remain. Initiatives such as the Minimum Information for Reporting Comet Assay (MIRCA) guidelines, alongside the integration of automated imaging and machine learning, are being implemented to address these challenges. With its growing applications in environmental toxicology, biomonitoring, and clinical research, the comet assay is increasingly recognized as a key tool in precision toxicology and personalized medicine. This review highlights major technical developments and emerging applications of the comet assay over the past fifteen years, discusses sources of experimental variability and strategies for optimization, and provides an update on current laboratory protocols for assessing DNA damage induced by genotoxic agents.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"154 ","pages":"Article 103899"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214977","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":"UBE2C promotes cell cycle progression and suppresses DNA damage-induced apoptosis in triple-negative breast cancer","authors":"Qin Hu ,&nbsp;Kewu Wang ,&nbsp;Chuanrong Chen ,&nbsp;Jian Ding ,&nbsp;Yang He ,&nbsp;Zhaoning Ji","doi":"10.1016/j.dnarep.2025.103901","DOIUrl":"10.1016/j.dnarep.2025.103901","url":null,"abstract":"<div><h3>Background</h3><div>Triple-negative breast cancer (TNBC), characterized by its aggressiveness, constitutes a unique breast cancer subtype, lacking effective targeted therapies. Its progression is often driven by cell cycle control dysfunction, impaired DNA damage handling, and resistance to apoptosis. Ubiquitin-conjugating enzyme E2C (UBE2C), an essential mitotic regulator, has been implicated in tumorigenesis and therapy resistance in several tumor types, but its relevance in TNBC is still poorly understood. This study focused on investigating the expression and functional importance of UBE2C in TNBC development.</div></div><div><h3>Methods</h3><div>UBE2C levels and their clinical relevance in TNBC were evaluated via transcriptomic data from TCGA and GTEx. Gene set enrichment analysis (GSEA) was performed to pinpoint UBE2C-associated biological pathways. Functional validation was conducted in MDA-MB-231 TNBC cell lines via qRT-PCR, Western blotting, flow cytometry, comet assay, and TUNEL staining to examine the effects of UBE2C modulation on cell cycle dynamics, DNA damage response, and apoptosis.</div></div><div><h3>Results</h3><div>UBE2C exhibited marked overexpression in TNBC tissues and cell lines relative to normal controls (P &lt; 0.01), and its high expression was correlated with reduced overall survival (P = 0.01). GSEA indicated enrichment of cell cycle and DNA repair pathways in UBE2C-high samples, while apoptosis pathways were suppressed (FDR &lt; 0.25). Functional assays demonstrated that UBE2C overexpression accelerated G1/S and G2/M transitions (P &lt; 0.01), reduced DNA damage accumulation (P &lt; 0.01), and suppressed apoptotic processes (P &lt; 0.01), while UBE2C knockdown elicited the opposite effects.</div></div><div><h3>Conclusion</h3><div>UBE2C promotes TNBC cell survival through modulation of cell cycle progression, DNA repair mechanisms, and apoptosis signaling. These results suggested that UBE2C could be considered a promising biomarker and therapeutic target, particularly in combination with DNA-damaging agents for personalized TNBC therapy.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"154 ","pages":"Article 103901"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294840","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":"PARP enzyme synthesis of protein-free poly(ADP-ribose): Implications for DNA damage signaling and repair","authors":"Marie-France Langelier,&nbsp;John M. Pascal","doi":"10.1016/j.dnarep.2025.103898","DOIUrl":"10.1016/j.dnarep.2025.103898","url":null,"abstract":"<div><div>Poly(ADP-ribose) or PAR is a versatile signaling molecule with a broad impact on human biology. PAR is a prominent indicator of cellular DNA damage and genomic transactions such as replication and transcription. Canonically, human PARP enzymes create PAR as a modification on proteins. Recently, PARP enzymes were found to create free PAR molecules that are not attached to protein. Free PAR has been implicated in cell death signaling, but the production of free PAR was assumed to be generated by glycohydrolases breaking down protein-linked PAR into smaller fragments. The direct de novo production of free PAR by PARP1 occurs alongside the synthesis of protein-linked PAR in response to DNA damage, suggesting a more prevalent role for free PAR in DNA damage signaling. This review outlines the discovery of free PAR synthesis in biochemical reactions and in cellular models of the DNA damage response. The implications for this finding are summarized in the context of DNA damage signaling and associated processes of biomolecular condensate formation and Parthanatos cell death signaling.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"154 ","pages":"Article 103898"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217764","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":"Mechanistic insights into RAD51-mediated nucleosome binding and remodeling in homologous recombination","authors":"Takuro Shioi ,&nbsp;Suguru Hatazawa ,&nbsp;Yoshimasa Takizawa ,&nbsp;Hitoshi Kurumizaka","doi":"10.1016/j.dnarep.2025.103891","DOIUrl":"10.1016/j.dnarep.2025.103891","url":null,"abstract":"<div><div>Eukaryotic cells organize their genomic DNA into chromatin to achieve both compact packaging and precise regulation of essential processes, including DNA repair. Depending on the type of damage, distinct repair pathways are activated through the targeted recruitment of repair factors to chromatin. RAD51 is the central recombinase in homologous recombination (HR) and forms nucleoprotein filaments, but its mode of chromatin engagement has remained elusive. In this review, we summarize recent progress in the structural and biochemical understanding of DNA repair within chromatin, with a particular focus on RAD51 and its role in HR. Specifically, we review newly determined cryo-electron microscopy (cryo-EM) structures of RAD51 bound to nucleosomes, revealing how RAD51 assembles on chromatin, recognizes DNA damage sites, and remodels nucleosomes into filamentous intermediates. We summarize current insights into how HR-associated proteins regulate RAD51 activity on chromatin, ensuring the fidelity of each step in HR. We conclude by outlining future directions for elucidating the downstream mechanisms of RAD51-mediated HR in the chromatin context.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"154 ","pages":"Article 103891"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088633","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":"Insight into meiotic DNA end resection: Mechanisms and regulation","authors":"Soonjoung Kim ,&nbsp;Hasan F. Alnaser ,&nbsp;Scott Keeney ,&nbsp;Hajime Murakami","doi":"10.1016/j.dnarep.2025.103886","DOIUrl":"10.1016/j.dnarep.2025.103886","url":null,"abstract":"<div><div>Meiosis generates reproductive cells with a reduced genome complement, with most species using homologous recombination to promote accurate meiotic chromosome segregation and to generate genetic diversity among offspring. A critical step in homologous recombination is DNA end resection, in which DNA double-strand breaks (DSBs) are processed by nucleases to yield the 3′ single-stranded DNA (ssDNA) needed for homology search and strand invasion. DSB resection in nonmeiotic contexts has been extensively studied, but meiotic resection is less well understood. We provide here a review of studies elucidating the mechanism and regulation of resection during meiosis, covering similarities and differences from resection in mitotically dividing cells. The nucleases that carry out resection are discussed, along with resection-modulating factors such as DNA damage signaling and chromatin structure. We focus on the budding yeast <em>Saccharomyces cerevisiae</em> and on mouse, for which the most information is currently available, but also describe studies in other species that point to evolutionary conservation or divergence in this key process needed for genome integrity in the germline.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103886"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890231","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":"Editors’ note Penny Jeggo and Bennett Van Houten","authors":"Penny Jeggo,&nbsp;Bennett Van Houten","doi":"10.1016/j.dnarep.2025.103862","DOIUrl":"10.1016/j.dnarep.2025.103862","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103862"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565567","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":"Proofreading exonuclease activities of Polδ and Polε differentially contribute to the removal of chain-terminating nucleoside analogs","authors":"Eri Nishizawa ,&nbsp;Hiromori Ohkubo ,&nbsp;Ryotaro Kawasumi ,&nbsp;Masataka Tsuda ,&nbsp;Kouji Hirota","doi":"10.1016/j.dnarep.2025.103885","DOIUrl":"10.1016/j.dnarep.2025.103885","url":null,"abstract":"<div><div>Chain-terminating nucleoside analogs (CTNAs) are incorporated into genome during replication by replicative polymerase delta (Polδ) and epsilon (Polε), then inhibit DNA synthesis by preventing subsequent polymerization. The proofreading exonuclease activity of Polε removes the incorporated CTNAs, thereby contributing to cellular tolerance to these drugs. However, the contribution of Polδ’s proofreading exonuclease activity has not been clarified, nor has the relationship between Polδ and Polε been well understood. We here show that Polδ’s exonuclease activity contributes to the cellular tolerance to CTNAs, with the role of Polδ and Polε exonucleases differing depending on the kinds of CTNAs. We tested the sensitivity of <em>POLD1</em>^{<em>exo−/+</em>} cells to a CTNA, Ara-C, and found that expression of the exonuclease deficient Polδ sensitizes cells to Ara-C. Furthermore, the exonuclease deficient Polδ reduced cell viability upon Ara-C to the same extent in both Polε exonuclease-proficient and -deficient cells, indicating that these two polymerases independently contribute to cellular tolerance to Ara-C. In contrast, wild-type, <em>POLD1</em>^{<em>exo−/+</em>}, and <em>POLE1</em>^{<em>exo−/−</em>} cells exhibited similar sensitivity to ddC, AZT, and alovudine, whilst <em>POLD1</em>^{<em>exo−/+</em>}/<em>POLE1</em>^{<em>exo−/−</em>} cells were considerably more sensitive compared with these cells, indicating that Polδ and Polε compensate for each other. Finally, we found that exonuclease activities of replicative polymerases cannot remove ACV from the end of nascent DNA. Taken together, our findings show that CTNAs have a differential impact on the replication fork, and the requirement of the exonuclease activities of replicative polymerases varies depending on the kinds of CTNAs.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103885"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144864214","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":"Corrigendum to “Unveiling cGAS mechanisms: Insights into DNA damage and immune sensing in cancer” [DNA Repair 152 (2025) 103868]","authors":"Min-Guk Cho ,&nbsp;Gaorav P. Gupta","doi":"10.1016/j.dnarep.2025.103878","DOIUrl":"10.1016/j.dnarep.2025.103878","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103878"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769462","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 B cell dilemma: Diversity or fidelity?","authors":"Maria Berruezo-Llacuna ,&nbsp;Eleni Kabrani ,&nbsp;Michela Di Virgilio","doi":"10.1016/j.dnarep.2025.103888","DOIUrl":"10.1016/j.dnarep.2025.103888","url":null,"abstract":"<div><div>The ability of B lymphocytes to diversify immunoglobulin (<em>Ig</em>) genes is central to the generation of high-affinity, class-switched antibodies and the establishment of effective humoral immunity. This diversification is achieved through three DNA remodeling processes that occur at defined stages of B cell development and maturation: V(D)J recombination, somatic hypermutation (SHM), and class switch recombination (CSR). These reactions all rely on the induction of programmed DNA lesions at <em>Ig</em> genes and their productive resolution by ubiquitous DNA repair pathways. However, such physiological sources of genotoxic stress render B cells vulnerable to genome instability, including mutations and chromosomal translocations that drive malignancies. Therefore, B cells have evolved complex regulatory networks that ensure efficient <em>Ig</em> gene diversification while minimizing the risk of unproductive or deleterious repair outcomes. In this review, we integrate foundational studies with recent mechanistic advances to outline how B cells exploit, coordinate, and constrain DNA repair to balance immune receptor diversification with the preservation of genome integrity.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103888"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989057","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}