DNA Repair最新文献

{"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":"2025-02-19","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":"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":"2025-02-17","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":"Pathological modulation of genome maintenance by cancer/testes antigens (CTAs)","authors":"Cyrus Vaziri ,&nbsp;Karly Forker ,&nbsp;Xingyuan Zhang ,&nbsp;Di Wu ,&nbsp;Pei Zhou ,&nbsp;Jessica L. Bowser","doi":"10.1016/j.dnarep.2025.103818","DOIUrl":"10.1016/j.dnarep.2025.103818","url":null,"abstract":"<div><div>The Cancer Testis Antigens (CTAs) are a group of germ cell proteins that are absent from normal somatic cells yet aberrantly expressed in many cancer cells. When mis-expressed in cancer cells, many CTAs promote tumorigenic characteristics including genome instability, DNA damage tolerance and therapy resistance. Here we highlight some of the CTAs for which their roles in genome maintenance in cancer cells are well established. We consider three broad CTA categories: (1) Melanoma Antigens (MAGEs) (2) Mitotic CTAs and (3) CTAs with roles in meiotic homologous recombination. Many cancer cells rely on CTAs to tolerate intrinsic and therapy-induced genotoxic stress. Therefore, CTAs represent molecular vulnerabilities of cancer cells and may provide opportunities for therapy. Owing to their high-level expression in tumors and absence from normal somatic cells, CTA-directed therapies could have a high level of specificity and would likely be devoid of side-effect toxicity.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"147 ","pages":"Article 103818"},"PeriodicalIF":3.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453632","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":"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}