DNA Repair最新文献

{"title":"Therapeutic targeting of mismatch repair proteins in triplet repeat expansion diseases","authors":"Paulina Marzec ,&nbsp;Madeleine Richer ,&nbsp;Robert S. Lahue","doi":"10.1016/j.dnarep.2025.103817","DOIUrl":"10.1016/j.dnarep.2025.103817","url":null,"abstract":"<div><div>Triplet repeat expansion diseases are a class of ∼20 inherited neurological disorders. Many of these diseases are debilitating, sometimes fatally so, and they have unfortunately proved difficult to treat. New compelling evidence shows that somatic repeat expansions in some diseases are essential to the pathogenic process, accelerating the age of onset and the rate of disease progression. Inhibiting somatic repeat expansions, therefore, provides a therapeutic opportunity to delay or block disease onset and/or slow progression. Several key aspects enhance the appeal of this therapeutic approach. First, the proteins responsible for promoting expansions are known from human genetics and model systems, obviating the need for lengthy target searches. They include the mismatch repair proteins MSH3, PMS1 and MLH3. Second, inhibiting or downregulating any of these three proteins is attractive due to their good safety profiles. Third, having three potential targets helps mitigate risk. Fourth, another protein, the nuclease FAN1, protects against expansions; in principle, increasing FAN1 activity could be therapeutic. Fifth, therapies aimed at inhibiting somatic repeat expansions could be used against several diseases that display this shared mechanistic feature, offering the opportunity for one treatment against multiple diseases. This review will address the underlying findings and the recent therapeutic advances in targeting MSH3, PMS1, MLH3 and FAN1 in triplet repeat expansion diseases.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"147 ","pages":"Article 103817"},"PeriodicalIF":3.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480169","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":"USP1 in regulation of DNA repair pathways","authors":"Amir Mahdi Mazloumi Aboukheili,&nbsp;Helen Walden","doi":"10.1016/j.dnarep.2025.103807","DOIUrl":"10.1016/j.dnarep.2025.103807","url":null,"abstract":"<div><div>Ubiquitin-specific protease 1 (USP1) is the founding member of the family of cysteine proteases that catalyse hydrolysis of the isopeptide bond between ubiquitin and targets. USP1 is often overexpressed in various cancers, and expression levels correlate with poor prognosis. USP1 and its partner USP1-associated Factor 1 (UAF1) are required for deubiquitinating monoubiquitin signals in DNA interstrand crosslink repair, and in Translesion synthesis, among others, and both proteins are subject to multiple regulations themselves. This review covers recent findings on the mechanisms and functions of USP1 in DNA repair, its regulation, and its potential as a target for therapeutic intervention.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103807"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030491","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":"Lawrence H. Thompson: A life of bikes, birds, and DNA repair (1941–2024)","authors":"Keith W. Caldecott","doi":"10.1016/j.dnarep.2025.103813","DOIUrl":"10.1016/j.dnarep.2025.103813","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103813"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070378","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":"Single-molecule toxicogenomics: Optical genome mapping of DNA-damage in nanochannel arrays","authors":"Tahir Detinis Zur ,&nbsp;Sapir Margalit ,&nbsp;Jonathan Jeffet ,&nbsp;Assaf Grunwald ,&nbsp;Sivan Fishman ,&nbsp;Zuzana Tulpová ,&nbsp;Yael Michaeli ,&nbsp;Jasline Deek ,&nbsp;Yuval Ebenstein","doi":"10.1016/j.dnarep.2025.103808","DOIUrl":"10.1016/j.dnarep.2025.103808","url":null,"abstract":"<div><div>Quantitative genomic mapping of DNA damage may provide insights into the underlying mechanisms of damage and repair. Sequencing based approaches are bound to the limitations of PCR amplification bias and read length which hamper both the accurate quantitation of damage events and the ability to map them to structurally complex genomic regions. Optical Genome mapping in arrays of parallel nanochannels allows physical extension and genetic profiling of millions of long genomic DNA fragments, and has matured to clinical utility for characterization of complex structural aberrations in cancer genomes. Here we present a new mapping modality, Repair-Assisted Damage Detection - Optical Genome Mapping (RADD-OGM), a method for single-molecule level mapping of DNA damage on a genome-wide scale. Leveraging ultra-long reads to assemble the complex structure of a sarcoma cell-line genome, we mapped the genomic distribution of oxidative DNA damage, identifying regions more susceptible to DNA oxidation. We also investigated DNA repair by allowing cells to repair chemically induced DNA damage, pinpointing locations of concentrated repair activity, and highlighting variations in repair efficiency. Our results showcase the potential of the method for toxicogenomic studies, mapping the effect of DNA damaging agents such as drugs and radiation, as well as following specific DNA repair pathways by selective induction of DNA damage. The facile integration with optical genome mapping enables performing such analyses even in highly rearranged genomes such as those common in many cancers, a challenging task for sequencing-based approaches.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103808"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018817","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":"Active genome integrity","authors":"Sukesh R. Bhaumik","doi":"10.1016/j.dnarep.2025.103816","DOIUrl":"10.1016/j.dnarep.2025.103816","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103816"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349370","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":"To divide or not to divide? NAC8 (SOG1) as a key regulator of DNA damage response in barley (Hordeum vulgare L.)","authors":"Miriam Szurman-Zubrzycka ,&nbsp;Anna Kocjan ,&nbsp;Emilia Spałek ,&nbsp;Monika Gajecka ,&nbsp;Paulina Jędrzejek ,&nbsp;Małgorzata Nawrot ,&nbsp;Iwona Szarejko ,&nbsp;Jolanta Kwasniewska","doi":"10.1016/j.dnarep.2025.103810","DOIUrl":"10.1016/j.dnarep.2025.103810","url":null,"abstract":"<div><div>We identified several new TILLING mutants of barley (<em>Hordeum vulgare</em> L.) with missense mutations in the <em>HvNAC8</em> gene, a homolog of the <em>SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1)</em> gene in <em>Arabidopsis thaliana</em>. In Arabidopsis, SOG1 is the primary regulator of the DNA Damage Response (DDR) pathway. We aimed to transfer this knowledge to barley, an agriculturally important crop. Our detailed analysis of the <em>hvnac8.k</em> mutant revealed an impaired DDR pathway. The <em>hvnac8.k</em> mutant accumulates DNA damage under genotoxic stress induced by zeocin, but it also shows increased DNA damage under normal growth conditions. Despite this, the frequency of dividing cells in the root meristem of the mutant treated with zeocin is much less affected than in the wild type. This suggests that the mutant bypasses the typical DDR regulation, where cell division is halted to allow DNA repair following damage. We also analyzed our mutant under aluminum (Al³⁺) stress. Aluminum ions, present in acidic soils that constitute approximately 50 % of arable land, are a common stressor that significantly reduce barley yield. Al³ ⁺ is known to cause DNA damage and activate DDR. Consequently, we aimed to assess whether the <em>hvnac8.k</em> phenotype could confer a beneficial effect under aluminum stress, a widespread agronomic challenge. Our findings suggest that modulation of the DDR pathway has the potential to improve aluminum tolerance in barley.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103810"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402909","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 Ataxia-telangiectasia mutated (ATM) is the most important gene for repairing the DNA in Myelodysplastic Neoplasm","authors":"Ronald Feitosa Pinheiro ,&nbsp;João Vitor Caetano Goes ,&nbsp;Leticia Rodrigues Sampaio ,&nbsp;Roberta Taiane Germano de Oliveira ,&nbsp;Sheila Coelho Soares Lima ,&nbsp;Cristiana Libardi Miranda Furtado ,&nbsp;Daniela de Paula Borges ,&nbsp;Marilia Braga Costa ,&nbsp;Cristiane da Silva Monte ,&nbsp;Natalia Feitosa Minete ,&nbsp;Silvia Maria Meira Magalhães ,&nbsp;Howard Lopes Ribeiro Junior","doi":"10.1016/j.dnarep.2024.103803","DOIUrl":"10.1016/j.dnarep.2024.103803","url":null,"abstract":"<div><div>Myelodysplastic Neoplasm (MDS) is a cancer associated with aging, often leading to acute myeloid leukemia (AML). One of its hallmarks is hypermethylation, particularly in genes responsible for DNA repair. This study aimed to evaluate the methylation and mutation status of DNA repair genes (single-strand - <em>XPA, XPC, XPG, CSA, CSB</em> and double-strand - <em>ATM, BRCA1, BRCA2, LIG4, RAD51</em>) in MDS across three patient cohorts (Cohort A-56, Cohort B-100, Cohort C-76), using methods like pyrosequencing, real-time PCR, immunohistochemistry, and mutation screening. Results showed that <em>XPA</em> had higher methylation in low-risk MDS compared to high-risk MDS. For double-strand repair genes, <em>ATM</em> displayed higher methylation in patients who transformed to AML (p = 0.016). <em>ATM</em> gene expression was downregulated in MDS compared to controls (p = 0.042). When patients were classified according to the WHO 2022 guidelines, <em>ATM</em> expression progressively decreased from low-risk subtypes (e.g., Hypoplastic MDS) to high-risk MDS and AML. Patients who transformed to AML had a higher 5mC/5hmC ratio compared to those who didn’t (p = 0.045). Additionally, poor cytogenetic risk patients had higher tissue methylation scores than those with good risk (p = 0.035). Analysis using the cBioPortal platform identified <em>ATM</em> as the most frequently mutated DNA repair gene, with various mutations, such as frameshift and missense, most of which were classified as oncogenic. The findings suggest that <em>ATM</em> is frequently silenced or downregulated in MDS due to methylation or mutations, contributing to the progression to AML. This highlights <em>ATM</em>'s potential role in the disease’s advancement and as a target for future therapeutic strategies.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103803"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061755","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":"Contents of Previous 3 Special Issues in this Series of Perspectives","authors":"","doi":"10.1016/j.dnarep.2025.103806","DOIUrl":"10.1016/j.dnarep.2025.103806","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103806"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973951","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":"Cutting edge perspectives in genome maintenance XI","authors":"Penelope Ann Jeggo","doi":"10.1016/j.dnarep.2025.103805","DOIUrl":"10.1016/j.dnarep.2025.103805","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103805"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967584","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 interplay between chromatin remodeling and DNA double-strand break repair: Implications for cancer biology and therapeutics","authors":"Liujun He ,&nbsp;Jaeyoung Moon ,&nbsp;Chenghui Cai ,&nbsp;Yalan Hao ,&nbsp;Hyorin Lee ,&nbsp;Wootae Kim ,&nbsp;Fei Zhao ,&nbsp;Zhenkun Lou","doi":"10.1016/j.dnarep.2025.103811","DOIUrl":"10.1016/j.dnarep.2025.103811","url":null,"abstract":"<div><div>Proper chromatin remodeling is crucial for many cellular physiological processes, including the repair of DNA double-strand break (DSB). While the mechanism of DSB repair is well understood, the connection between chromatin remodeling and DSB repair remains incompletely elucidated. In this review, we aim to highlight recent studies demonstrating the close relationship between chromatin remodeling and DSB repair. We summarize the impact of DSB repair on chromatin, including nucleosome arrangement, chromatin organization, and dynamics, and conversely, the role of chromatin architecture in regulating DSB repair. Additionally, we also summarize the contribution of chromatin remodeling complexes to cancer biology through DNA repair and discuss their potential as therapeutic targets for cancer.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"146 ","pages":"Article 103811"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030489","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}