DNA Repair最新文献

{"title":"LncRNA LINC01664 promotes cancer resistance through facilitating homologous recombination-mediated DNA repair","authors":"Jie Du ,&nbsp;Fuqiang Chen ,&nbsp;Zihan Chen ,&nbsp;Wenna Zhao ,&nbsp;Jianyu Wang ,&nbsp;Meijuan Zhou","doi":"10.1016/j.dnarep.2024.103770","DOIUrl":"10.1016/j.dnarep.2024.103770","url":null,"abstract":"<div><div>The intracellular responses to DNA double-strand breaks (DSB) repair are crucial for genomic stability and play an essential role in cancer resistance. In addition to canonical DSB repair proteins, long non-coding RNAs (lncRNAs) have been found to be involved in this sophisticated network. In the present study, we performed a loss-of-function screen for a customized siRNA Premix Library to identify lncRNAs that participate in homologous recombination (HR) process. Among the candidates, we identified LINC01664 as a novel lncRNA required for HR repair. Furthermore, LINC01664 knockdown significantly increased the sensitivity of cancer cells to DNA damage agents such as ionizing radiation and genotoxic drugs. Mechanistically, LINC01664 interacted with Sirt1 promoter and then activated Sirt1 transcription, which contributed to HR-mediated DNA damage repair. In summary, our findings revealed a new mechanism of LINC01664 in DNA damage repair, providing evidence for a potential therapeutic strategy for eliminating the treatment bottlenecks caused by cancer resistance to chemotherapy and radiotherapy.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"143 ","pages":"Article 103770"},"PeriodicalIF":3.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368005","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":"Evidence that DNA polymerase δ proofreads errors made by DNA polymerase α across the Saccharomyces cerevisiae nuclear genome","authors":"Sarah A. Marks ,&nbsp;Zhi-Xiong Zhou ,&nbsp;Scott A. Lujan ,&nbsp;Adam B. Burkholder ,&nbsp;Thomas A. Kunkel","doi":"10.1016/j.dnarep.2024.103768","DOIUrl":"10.1016/j.dnarep.2024.103768","url":null,"abstract":"<div><div>We show that the rates of single base substitutions, additions, and deletions across the nuclear genome are strongly increased in a strain harboring a mutator variant of DNA polymerase α combined with a mutation that inactivates the 3´-5´ exonuclease activity of DNA polymerase δ. Moreover, tetrad dissections attempting to produce a haploid triple mutant lacking Msh6, which is essential for DNA mismatch repair (MMR) of base•base mismatches made during replication, result in tiny colonies that grow very slowly and appear to be aneuploid and/or defective in oxidative metabolism. These observations are consistent with the hypothesis that during initiation of nuclear DNA replication, single-base mismatches made by naturally exonuclease-deficient DNA polymerase α are extrinsically proofread by DNA polymerase δ, such that in the absence of this proofreading, the mutation rate is strongly elevated. Several implications of these data are discussed, including that the mutational signature of defective extrinsic proofreading in yeast could appear in human tumors.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"143 ","pages":"Article 103768"},"PeriodicalIF":3.0,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323313","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":"Transcription reprogramming and endogenous DNA damage","authors":"Lei Li","doi":"10.1016/j.dnarep.2024.103754","DOIUrl":"10.1016/j.dnarep.2024.103754","url":null,"abstract":"<div><p>Transcription reprogramming is essential to carry out a variety of cell dynamics such as differentiation and stress response. During reprogramming of transcription, a number of adverse effects occur and potentially compromise genomic stability. Formaldehyde as an obligatory byproduct is generated in the nucleus via oxidative protein demethylation at regulatory regions, leading to the formation of DNA crosslinking damage. Elevated levels of transcription activities can result in the accumulation of unscheduled R-loop. DNA strand breaks can form if processed 5-methylcytosines are exercised by DNA glycosylase during imprint reversal. When cellular differentiation involves a large number of genes undergoing transcription reprogramming, these endogenous DNA lesions and damage-prone structures may pose a significant threat to genome stability. In this review, we discuss how DNA damage is formed during cellular differentiation, cellular mechanisms for their removal, and diseases associated with transcription reprogramming.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"142 ","pages":"Article 103754"},"PeriodicalIF":3.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130232","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":"Structure, function and evolution of the HerA subfamily proteins","authors":"Yiyang Sun ,&nbsp;Kaiying Cheng","doi":"10.1016/j.dnarep.2024.103760","DOIUrl":"10.1016/j.dnarep.2024.103760","url":null,"abstract":"<div><p>HerA is an ATP-dependent translocase that is widely distributed in archaea and some bacteria. It belongs to the HerA/FtsK translocase bacterial family, which is a subdivision of the RecA family. Currently, it is identified that HerA participates in the repair of DNA double-strand breaks (DSBs) or confers anti-phage defense by assembling other proteins into large complexes. In recent years, there has been a growing understanding of the bioinformatics, biochemistry, structure, and function of HerA subfamily members in both archaea and bacteria. This comprehensive review compares the structural disparities among diverse HerAs and elucidates their respective roles in specific life processes.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"142 ","pages":"Article 103760"},"PeriodicalIF":3.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137402","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":"Exploring the removal of Spo11 and topoisomerases from DNA breaks in S. cerevisiae by human Tyrosyl DNA Phosphodiesterase 2","authors":"Dominic Johnson ,&nbsp;Rachal M. Allison ,&nbsp;Elda Cannavo ,&nbsp;Petr Cejka ,&nbsp;Jon A. Harper ,&nbsp;Matthew J. Neale","doi":"10.1016/j.dnarep.2024.103757","DOIUrl":"10.1016/j.dnarep.2024.103757","url":null,"abstract":"<div><p>Meiotic recombination is initiated by DNA double-strand breaks (DSBs) created by Spo11, a type-II topoisomerase-like protein that becomes covalently linked to DSB ends. Whilst Spo11 oligos—the products of nucleolytic removal by Mre11—have been detected in several organisms, the lifetime of the covalent Spo11-DSB precursor has not been determined and may be subject to alternative processing. Here, we explore the activity of human Tyrosyl DNA Phosphodiesterase, TDP2—a protein known to repair DNA ends arising from abortive topoisomerase activity—on Spo11 DSBs isolated from <em>S. cerevisiae</em> cells. We demonstrate that TDP2 can remove Spo11 peptides from ssDNA oligos and dsDNA ends even in the presence of competitor genomic DNA. Interestingly, TDP2-processed DSB ends are refractory to resection by Exo1, suggesting that ssDNA generated by Mre11 may be essential <em>in vivo</em> to facilitate HR at Spo11 DSBs even if TDP2 were active. Moreover, although TDP2 can remove Spo11 peptides <em>in vitro</em>, TDP2 expression in meiotic cells was unable to remove Spo11 <em>in vivo</em>—contrasting its ability to aid repair of topoisomerase-induced DNA lesions. These results suggest that Spo11-DNA, but not topoisomerase-DNA cleavage complexes, are inaccessible to the TDP2 enzyme, perhaps due to occlusion by higher-order protein complexes at sites of meiotic recombination.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"142 ","pages":"Article 103757"},"PeriodicalIF":3.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137403","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":"Tolerating DNA damage by repriming: Gap filling in the spotlight","authors":"Tiya Jahjah ,&nbsp;Jenny K. Singh ,&nbsp;Vanesa Gottifredi ,&nbsp;Annabel Quinet","doi":"10.1016/j.dnarep.2024.103758","DOIUrl":"10.1016/j.dnarep.2024.103758","url":null,"abstract":"<div><p>Timely and accurate DNA replication is critical for safeguarding genome integrity and ensuring cell viability. Yet, this process is challenged by DNA damage blocking the progression of the replication machinery. To counteract replication fork stalling, evolutionary conserved DNA damage tolerance (DDT) mechanisms promote DNA damage bypass and fork movement. One of these mechanisms involves “skipping” DNA damage through repriming downstream of the lesion, leaving single-stranded DNA (ssDNA) gaps behind the advancing forks (also known as post-replicative gaps). In vertebrates, repriming in damaged leading templates is proposed to be mainly promoted by the primase and polymerase PRIMPOL. In this review, we discuss recent advances towards our understanding of the physiological and pathological conditions leading to repriming activation in human models, revealing a regulatory network of PRIMPOL activity. Upon repriming by PRIMPOL, post-replicative gaps formed can be filled-in by the DDT mechanisms translesion synthesis and template switching. We discuss novel findings on how these mechanisms are regulated and coordinated in time to promote gap filling. Finally, we discuss how defective gap filling and aberrant gap expansion by nucleases underlie the cytotoxicity associated with post-replicative gap accumulation. Our increasing knowledge of this repriming mechanism – from gap formation to gap filling – is revealing that targeting the last step of this pathway is a promising approach to exploit post-replicative gaps in anti-cancer therapeutic strategies.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"142 ","pages":"Article 103758"},"PeriodicalIF":3.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424001344/pdfft?md5=9d0db51b43887b593c7fd2ff414ca0be&pid=1-s2.0-S1568786424001344-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137404","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":"Stressed? Break-induced replication comes to the rescue!","authors":"Rosemary S. Lee ,&nbsp;Jerzy M. Twarowski ,&nbsp;Anna Malkova","doi":"10.1016/j.dnarep.2024.103759","DOIUrl":"10.1016/j.dnarep.2024.103759","url":null,"abstract":"<div><p>Break-induced replication (BIR) is a homologous recombination (HR) pathway that repairs one-ended DNA double-strand breaks (DSBs), which can result from replication fork collapse, telomere erosion, and other events. Eukaryotic BIR has been mainly investigated in yeast, where it is initiated by invasion of the broken DNA end into a homologous sequence, followed by extensive replication synthesis proceeding to the chromosome end. Multiple recent studies have described BIR in mammalian cells, the properties of which show many similarities to yeast BIR. While HR is considered as “error-free” mechanism, BIR is highly mutagenic and frequently leads to chromosomal rearrangements—genetic instabilities known to promote human disease. In addition, it is now recognized that BIR is highly stimulated by replication stress (RS), including RS constantly present in cancer cells, implicating BIR as a contributor to cancer genesis and progression. Here, we discuss the past and current findings related to the mechanism of BIR, the association of BIR with replication stress, and the destabilizing effects of BIR on the eukaryotic genome. Finally, we consider the potential for exploiting the BIR machinery to develop anti-cancer therapeutics.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"142 ","pages":"Article 103759"},"PeriodicalIF":3.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142147159","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":"C-terminal residues of DNA polymerase β and E3 ligase required for ubiquitin-linked proteolysis of oxidative DNA-protein crosslinks","authors":"Jason L. Quiñones ,&nbsp;Meiyi Tang ,&nbsp;Qingming Fang ,&nbsp;Robert W. Sobol ,&nbsp;Bruce Demple","doi":"10.1016/j.dnarep.2024.103756","DOIUrl":"10.1016/j.dnarep.2024.103756","url":null,"abstract":"<div><p>Free radicals produce in DNA a large variety of base and deoxyribose lesions that are corrected by the base excision DNA repair (BER) system. However, the C1′-oxidized abasic residue 2-deoxyribonolactone (dL) traps DNA repair lyases in covalent DNA-protein crosslinks (DPC), including the core BER enzyme DNA polymerase beta (Polβ). Polβ-DPC are rapidly processed in mammalian cells by proteasome-dependent digestion. Blocking the proteasome causes oxidative Polβ-DPC to accumulate in a ubiquitylated form, and this accumulation is toxic to human cells. In the current study, we investigated the mechanism of Polβ-DPC processing in cells exposed to the dL-inducing oxidant 1,10-copper-ortho-phenanthroline. Alanine substitution of either or both of two Polβ C-terminal residues, lysine-206 and lysine-244, enhanced the accumulation of mutant Polβ-DPC relative to the wild-type protein, and removal of the mutant DPC was diminished. Substitution of the N-terminal lysines 41, 61, and 81 did not affect Polβ-DPC processing. For Polβ with the C-terminal lysine substitutions, the amount of ubiquitin in the stabilized DPC was lowered by ∼40 % relative to wild-type Polβ. Suppression of the HECT domain-containing E3 ubiquitin ligase TRIP12 augmented the formation of oxidative Polβ-DPC and prevented Polβ-DPC removal in oxidant-treated cells. Consistent with the toxicity of accumulated oxidative Polβ-DPC, <em>TRIP12</em> knockdown increased oxidant-mediated cytotoxicity. Thus, ubiquitylation of lysine-206 and lysine-244 by TRIP12 is necessary for digestion of Polβ-DPC by the proteasome as the rapid first steps of DPC repair to prevent their cytotoxic accumulation. Understanding how DPC formed with Polβ or other AP lyases are repaired <em>in vivo</em> is an important step in revealing how cells cope with the toxic potential of such adducts.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"143 ","pages":"Article 103756"},"PeriodicalIF":3.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424001320/pdfft?md5=44abc53da2212e691b264ca02a64057c&pid=1-s2.0-S1568786424001320-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142147160","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":"DNA mismatch repair controls the mutagenicity of Polymerase ζ-dependent translesion synthesis at methylated guanines","authors":"Anastasia Tsaalbi-Shtylik ,&nbsp;Cécile Mingard ,&nbsp;Michael Räz ,&nbsp;Rurika Oka ,&nbsp;Freek Manders ,&nbsp;Ruben Van Boxtel ,&nbsp;Niels De Wind ,&nbsp;Shana J. Sturla","doi":"10.1016/j.dnarep.2024.103755","DOIUrl":"10.1016/j.dnarep.2024.103755","url":null,"abstract":"<div><p>By replicating damaged nucleotides, error-prone DNA translesion synthesis (TLS) enables the completion of replication, albeit at the expense of fidelity. TLS of helix-distorting DNA lesions, that usually have reduced capacity of basepairing, comprises insertion opposite the lesion followed by extension, the latter in particular by polymerase ζ (Pol ζ). However, little is known about involvement of Pol ζ in TLS of non- or poorly-distorting, but miscoding, lesions such as <em>O</em>⁶-methyldeoxyguanosine (<em>O</em>⁶-medG). Using purified Pol ζ we describe that the enzyme can misincorporate thymidine opposite <em>O</em>⁶-medG and efficiently extend from terminal mismatches, suggesting its involvement in the mutagenicity of <em>O</em>⁶-medG. Surprisingly, O6-medG lesions induced by the methylating agent <em>N</em>-methyl-<em>N’</em>-nitro-<em>N</em>-nitrosoguanidine (MNNG) appeared more, rather than less, mutagenic in Pol ζ-deficient mouse embryonic fibroblasts (MEFs) than in wild type MEFs. This suggested that <em>in vivo</em> Pol ζ participates in non-mutagenic TLS of <em>O</em>⁶-medG. However, we found that the Pol ζ-dependent misinsertions at O⁶-medG lesions are efficiently corrected by DNA mismatch repair (MMR), which masks the error-proneness of Pol ζ. We also found that the MNNG-induced mutational signature is determined by the adduct spectrum, and modulated by MMR. The signature mimicked single base substitution signature 11 in the catalogue of somatic mutations in cancer, associated with treatment with the methylating drug temozolomide. Our results unravel the individual roles of the major contributors to methylating drug-induced mutagenesis. Moreover, these results warrant caution as to the classification of TLS as mutagenic or error-free based on <em>in vitro</em> data or on the analysis of mutations induced in MMR-proficient cells.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"142 ","pages":"Article 103755"},"PeriodicalIF":3.0,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424001319/pdfft?md5=adfde92ff0c0aeab09681d19792fe1bd&pid=1-s2.0-S1568786424001319-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097003","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":"From rest to repair: Safeguarding genomic integrity in quiescent cells","authors":"Chin Wei Brian Leung ,&nbsp;Jacob Wall ,&nbsp;Fumiko Esashi","doi":"10.1016/j.dnarep.2024.103752","DOIUrl":"10.1016/j.dnarep.2024.103752","url":null,"abstract":"<div><p>Quiescence is an important non-pathological state in which cells pause cell cycle progression temporarily, sometimes for decades, until they receive appropriate proliferative stimuli. Quiescent cells make up a significant proportion of the body, and maintaining genomic integrity during quiescence is crucial for tissue structure and function. While cells in quiescence are spared from DNA damage associated with DNA replication or mitosis, they are still exposed to various sources of endogenous DNA damage, including those induced by normal transcription and metabolism. As such, it is vital that cells retain their capacity to effectively repair lesions that may occur and return to the cell cycle without losing their cellular properties. Notably, while DNA repair pathways are often found to be downregulated in quiescent cells, emerging evidence suggests the presence of active or differentially regulated repair mechanisms. This review aims to provide a current understanding of DNA repair processes during quiescence in mammalian systems and sheds light on the potential pathological consequences of inefficient or inaccurate repair in quiescent cells.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"142 ","pages":"Article 103752"},"PeriodicalIF":3.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424001289/pdfft?md5=3dc5a03deaf6546e0768ebe65c2c296c&pid=1-s2.0-S1568786424001289-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012927","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}