DNA Repair最新文献_第3页

The interplay between chromatin remodeling and DNA double-strand break repair: Implications for cancer biology and therapeutics

IF 3 3区生物学

DNA Repair Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103811

Liujun He , Jaeyoung Moon , Chenghui Cai , Yalan Hao , Hyorin Lee , Wootae Kim , Fei Zhao , Zhenkun Lou

引用次数: 0

Small-molecule activator of SMUG1 enhances repair of pyrimidine lesions in DNA

IF 3 3区生物学

DNA Repair Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103809

Yixuan Gao , Lisa McPherson , Shanthi Adimoolam , Samyuktha Suresh , David L. Wilson , Ishani Das , Elizabeth R. Park , Christine S.C. Ng , Yong Woong Jun , James M. Ford , Eric T. Kool

{"title":"Small-molecule activator of SMUG1 enhances repair of pyrimidine lesions in DNA","authors":"Yixuan Gao , Lisa McPherson , Shanthi Adimoolam , Samyuktha Suresh , David L. Wilson , Ishani Das , Elizabeth R. Park , Christine S.C. Ng , Yong Woong Jun , James M. Ford , Eric T. Kool","doi":"10.1016/j.dnarep.2025.103809","DOIUrl":"10.1016/j.dnarep.2025.103809","url":null,"abstract":"<div><div>A potentially promising approach to targeted cancer prevention in genetically at-risk populations is the pharmacological upregulation of DNA repair pathways. SMUG1 is a base excision repair enzyme that ameliorates adverse genotoxic and mutagenic effects of hydrolytic and oxidative damage to pyrimidines. Here we describe the discovery and initial cellular activity of a small-molecule activator of SMUG1. Screening of a kinase inhibitor library and iterative rounds of structure-activity relationship studies produced compound <strong>40</strong> (SU0547), which activates SMUG1 by as much as 350 ± 60 % <em>in vitro</em> at 100 nM, with an AC<sub>50</sub> of 4.3 ± 1.1 µM. To investigate the effect of compound <strong>40</strong> on endogenous SMUG1, we performed <em>in vitro</em> cell-based experiments with 5-hydroxymethyl-2’-deoxyuridine (5-hmdU), a pyrimidine oxidation product that is selectively removed by SMUG1. In several human cell lines, compound <strong>40</strong> at 3–5 µM significantly reduces the cytotoxicity of 5-hmdU and decreases levels of double-strand breaks induced by the damaged nucleoside. We conclude that the SMUG1 activator compound <strong>40</strong> is a useful tool to study the mechanisms of 5-hmdU toxicity and the potentially beneficial effects of suppressing damage to pyrimidines in cellular DNA.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103809"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070379","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}

引用次数: 0

DNA repair pathways in the mitochondria

IF 3 3区生物学

DNA Repair Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103814

Dillon E. King, William C. Copeland

引用次数: 0

Long-range PCR as a tool for evaluating mitochondrial DNA damage: Principles, benefits, and limitations of the technique

IF 3 3区生物学

DNA Repair Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103812

Artem P. Gureev, Veronika V. Nesterova, Irina S. Sadovnikova

{"title":"Long-range PCR as a tool for evaluating mitochondrial DNA damage: Principles, benefits, and limitations of the technique","authors":"Artem P. Gureev, Veronika V. Nesterova, Irina S. Sadovnikova","doi":"10.1016/j.dnarep.2025.103812","DOIUrl":"10.1016/j.dnarep.2025.103812","url":null,"abstract":"<div><div>Mitochondrial DNA (mtDNA) is often more susceptible to damage compared to nuclear DNA. This is due to its localization in the mitochondrial matrix, where a large portion of reactive oxygen species are produced. Mitochondria do not have histones and mtDNA is only slightly protected by histone-like proteins and is believed to have less efficient repair mechanisms. In this review, we discuss the long-range PCR method, which allows for the effective detection of mtDNA damage. The method is based on the assumption that various types of DNA lesions can interfere the progress of DNA polymerase, resulting in reduced amplification efficiency. It can be used to estimate the number of additional (above background) lesions in mtDNA. The review outlines the evolution of the methodology, its variations, applications in a wide range of model organisms, the advantages of the method and its limitations, as well as ways to overcome these limitations. Over the past two decades, the use of long-range PCR has allowed the study of mtDNA repair mechanisms, the characteristics of mitochondrial genome damage in various neurodegenerative diseases, aging, ischemic and oncological processes, as well as in anticancer therapy. The assessment of mtDNA damage has also been proposed for use in environmental biomonitoring. This review provides a critical evaluation of the various variations of this method, summarizes the accumulated data, and discusses the role of mtDNA damage in different organs at the organismal level.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103812"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030488","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}

引用次数: 0

Spontaneous and salt stress-induced molecular instability in the progeny of MSH7 deficient Arabidopsis thaliana plants 拟南芥MSH7缺陷植株后代的自发分子不稳定性和盐胁迫诱导的分子不稳定性

IF 3 3区生物学

DNA Repair Pub Date : 2025-01-01 DOI: 10.1016/j.dnarep.2024.103801

Michelle C. Chirinos-Arias , Claudia P. Spampinato

{"title":"Spontaneous and salt stress-induced molecular instability in the progeny of MSH7 deficient Arabidopsis thaliana plants","authors":"Michelle C. Chirinos-Arias , Claudia P. Spampinato","doi":"10.1016/j.dnarep.2024.103801","DOIUrl":"10.1016/j.dnarep.2024.103801","url":null,"abstract":"<div><div>The MSH7 protein is a binding partner of MSH2 forming the MutSγ complex. This complex contributes to the plant mismatch repair (MMR) system by recognizing DNA base-base mismatches. Here, we evaluated the impact of MSH7 on genetic diversity of the tenth generation (G<sub>10</sub>) of wild type and MSH7 deficient <em>Arabidopsis thaliana</em> plants before and after two days exposure to 100 mM NaCl. Genetic diversity was assessed using inter simple sequence repeats (ISSR) and high-resolution melting (HRM) analyses. ISSR analyses revealed a 6.7 % or 5.8 % average polymorphism in the G<sub>10</sub> of wild type before and after a short-term salt stress, respectively, and a 64.4 % or 72.1 % average polymorphism in the G<sub>10</sub> of <em>msh7</em> mutant plants before and after salt treatment, respectively. Interestingly, several ISSR markers showed different polymorphism patterns after salt stress compared with the control before treatment. We next compared the percentage of the G<sub>10</sub> of wild type and <em>msh7</em> seedlings with polymorphic bands. Statistically significant differences between genotypes but not due to the salt treatment were observed. In addition, co-amplification at lower temperature-PCR followed by HRM analysis was performed. Of the five assayed HRM loci, two loci allowed the discrimination of fragment alleles between genotypes and two loci, between conditions. We conclude that MSH7 deficient <em>A. thaliana</em> mutants accumulated mutations over 10 generations, and that two days of salt stress caused a further increase in new mutations, thus enhancing genetic diversity that may favor new traits associated with stress tolerance, fitness, and adaptation.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103801"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866851","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}

引用次数: 0

Mechanisms of tandem duplication in the cancer genome 癌症基因组串联复制的机制。

IF 3 3区生物学

DNA Repair Pub Date : 2025-01-01 DOI: 10.1016/j.dnarep.2024.103802

Ralph Scully , Dominik Glodzik , Francesca Menghi , Edison T. Liu , Cheng-Zhong Zhang

引用次数: 0

The Shu complex is an ATPase that regulates Rad51 filaments during homologous recombination in the DNA damage response Shu复合物是一种atp酶，在DNA损伤反应中的同源重组过程中调节Rad51细丝。

IF 3 3区生物学

DNA Repair Pub Date : 2025-01-01 DOI: 10.1016/j.dnarep.2024.103792

Sam S.H. Chu, Guangxin Xing, Vikash K. Jha , Hong Ling

{"title":"The Shu complex is an ATPase that regulates Rad51 filaments during homologous recombination in the DNA damage response","authors":"Sam S.H. Chu, Guangxin Xing, Vikash K. Jha , Hong Ling","doi":"10.1016/j.dnarep.2024.103792","DOIUrl":"10.1016/j.dnarep.2024.103792","url":null,"abstract":"<div><div>Rad51 filaments are Rad51-coated single-stranded DNA and essential in homologous recombination (HR). The yeast Shu complex (Shu) is a conserved regulator of homologous recombination, working through its modulation on Rad51 filaments to direct HR-associated DNA damage response. However, the biochemical properties of Shu remain unclear, which hinders molecular insights into Shu’s role in HR and the DNA damage response. In this work, we biochemically characterized Shu and analyzed its molecular actions on single-stranded DNA and Rad51 filaments. First, we revealed that Shu preferentially binds fork-shaped DNA with 20nt ssDNA components. Then, we identified and validated, through site-specific mutagenesis, that Shu is an ATPase and hydrolyzes ATP in a DNA-dependent manner. Furthermore, we showed that Shu interacts with ssDNA and Rad51 filaments and alters the properties of ssDNA and the filaments with a 5′-3′ polarity. The alterations depend on the ATP hydrolysis of Shu, suggesting that the ATPase activity of Shu is important in regulating its functions. The preference of Shu for acting on the 5′ end of Rad51 filaments aligns with the observation that Shu promotes lesion bypass at the lagging strand of a replication fork. Our work on Shu, a prototype modulator of Rad51 filaments in eukaryotes, provides a general molecular mechanism for Rad51-mediated error-free DNA lesion bypass.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103792"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796722","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}

引用次数: 0

MeCP2 deficiency leads to the γH2AX nano foci expansion after ionizing radiation MeCP2缺乏导致电离辐射后γ - h2ax纳米焦扩展。

IF 3 3区生物学

DNA Repair Pub Date : 2025-01-01 DOI: 10.1016/j.dnarep.2024.103790

Hikaru Okumura , Ryota Hayashi , Daiki Unami , Mayu Isono , Motohiro Yamauchi , Kensuke Otsuka , Yu Kato , Takahiro Oike , Yuki Uchihara , Atsushi Shibata

{"title":"MeCP2 deficiency leads to the γH2AX nano foci expansion after ionizing radiation","authors":"Hikaru Okumura , Ryota Hayashi , Daiki Unami , Mayu Isono , Motohiro Yamauchi , Kensuke Otsuka , Yu Kato , Takahiro Oike , Yuki Uchihara , Atsushi Shibata","doi":"10.1016/j.dnarep.2024.103790","DOIUrl":"10.1016/j.dnarep.2024.103790","url":null,"abstract":"<div><div>DNA double-strand breaks (DSBs) trigger the recruitment of repair protein and promote signal transduction through posttranslational modifications such as phosphorylation. After DSB induction, ataxia telangiectasia mutated (ATM) phosphorylates H2AX on chromatin surrounds the mega-base pairs proximal to the DSBs. Advanced super-resolution microscopic technology has demonstrated the formation of γH2AX nano foci as a unit of nano domain comprised of multiple nucleosomes. The formation of γH2AX nano foci could be potentially affected by pre-existing chromatin structure prior to DSB induction; however, it remains unclear whether chromatin status around DSBs influences the formation of γH2AX nano foci. In this study, to investigate γH2AX nano foci formation in the context of chromatin relaxation, γH2AX nano foci were examined following the depletion of MeCP2, which is a factor promoting chromatin condensation. Remarkably, by using super-resolution imaging analysis, we found that the volume of γH2AX nano foci cluster in MeCP2-depleted cells was significantly greater than that in control cells, both 5 and 30 min after ionizing radiation (IR). Corresponding to the increased volume size, the number of γH2AX nano foci per cluster was greater than that in control cells, while the distance of each nano focus within foci clusters remained unchanged. These findings suggest that relaxed chromatin condition by MeCP2 depletion facilitates faster and more extensive γH2AX nano foci formation after IR. Collectively, our super-resolution analysis suggests that the chromatin status surrounding DSBs influences the expansion of γH2AX nano foci formation, thus, potentially influencing the DSB repair and signaling.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103790"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796703","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}

引用次数: 0

Corrigendum to “BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination” [DNA Repair 115 (2022) 103331] “BCL-3缺失通过靶向同源重组使结直肠癌细胞对DNA损伤敏感”[DNA修复115(2022)103331]的更正。

IF 3 3区生物学

DNA Repair Pub Date : 2025-01-01 DOI: 10.1016/j.dnarep.2024.103800

Christopher Parker , Adam C. Chambers , Dustin J. Flanagan , Jasmine Wing Yu Ho , Tracey J. Collard , Greg Ngo , Duncan M. Baird , Penny Timms , Rhys G. Morgan , Owen J. Sansom , Ann C. Williams

引用次数: 0

The HNH endonuclease domain of the giant virus MutS7 specifically binds to branched DNA structures with single-stranded regions 巨型病毒MutS7的HNH内切酶结构域特异性地与单链区域的支链DNA结构结合。

IF 3 3区生物学

DNA Repair Pub Date : 2025-01-01 DOI: 10.1016/j.dnarep.2024.103804

Satoshi Yoshioka , Hirochika Kurazono , Koki Ohshita , Kenji Fukui , Masaharu Takemura , Shin-Ichiro Kato , Kouhei Ohnishi , Takato Yano , Taisuke Wakamatsu

{"title":"The HNH endonuclease domain of the giant virus MutS7 specifically binds to branched DNA structures with single-stranded regions","authors":"Satoshi Yoshioka , Hirochika Kurazono , Koki Ohshita , Kenji Fukui , Masaharu Takemura , Shin-Ichiro Kato , Kouhei Ohnishi , Takato Yano , Taisuke Wakamatsu","doi":"10.1016/j.dnarep.2024.103804","DOIUrl":"10.1016/j.dnarep.2024.103804","url":null,"abstract":"<div><div>Most giant viruses including <em>Mimiviridae</em> family build large viral factories within the host cytoplasms. These giant viruses are presumed to possess specific genes that enable the rapid and massive replication of their large double-stranded DNA genomes within viral factories. It has been revealed that a functionally uncharacterized protein, MutS7, is expressed during the operational phase of the viral factory. MutS7 contains an N-terminal mismatched DNA-binding domain, which is similar to the mismatched DNA-recognizing protein MutS1, and a unique C-terminal HNH endonuclease domain absent in other MutS family proteins. MutS7 gene of the genus <em>Mimivirus</em> of the family <em>Mimiviridae</em> is encoded in the locus that is responsible for resistance against infection of a virophage. In the present study, we characterized the MutS7 HNH domain of <em>Mimivirus shirakomae.</em> The HNH domain preferentially bound to branched DNA structures containing single-stranded regions, especially the displacement-loop structure, which is a primary intermediate in homologous/homeologous recombination, rather than to linear DNAs and branched DNAs lacking single-stranded regions. However, the HNH domain exhibited no endonuclease activity. The site-directed mutagenesis analysis revealed that the Cys4-type zinc finger of the HNH domain was not essential, but was important for the DNA binding. Given that giant virus MutS7 contains a mismatch-binding domain in addition to the HNH domain, we propose that giant virus MutS7 may suppress homeologous recombination in the viral factory.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103804"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916525","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}

引用次数: 0