DNA Repair最新文献

{"title":"Oncometabolite 2-hydroxyglutarate suppresses basal protein levels of DNA polymerase beta that enhances alkylating agent and PARG inhibition induced cytotoxicity","authors":"Kate M. Saville ,&nbsp;Rasha Q. Al-Rahahleh ,&nbsp;Aisha H. Siddiqui ,&nbsp;Morgan E. Andrews ,&nbsp;Wynand P. Roos ,&nbsp;Christopher A. Koczor ,&nbsp;Joel F. Andrews ,&nbsp;Faisal Hayat ,&nbsp;Marie E. Migaud ,&nbsp;Robert W. Sobol","doi":"10.1016/j.dnarep.2024.103700","DOIUrl":"10.1016/j.dnarep.2024.103700","url":null,"abstract":"<div><p>Mutations in isocitrate dehydrogenase isoform 1 (<em>IDH1</em>) are primarily found in secondary glioblastoma (GBM) and low-grade glioma but are rare in primary GBM. The standard treatment for GBM includes radiation combined with temozolomide, an alkylating agent. Fortunately, <em>IDH1</em> mutant gliomas are sensitive to this treatment, resulting in a more favorable prognosis. However, it’s estimated that up to 75 % of <em>IDH1</em> mutant gliomas will progress to WHO grade IV over time and develop resistance to alkylating agents. Therefore, understanding the mechanism(s) by which <em>IDH1</em> mutant gliomas confer sensitivity to alkylating agents is crucial for developing targeted chemotherapeutic approaches. The base excision repair (BER) pathway is responsible for repairing most base damage induced by alkylating agents. Defects in this pathway can lead to hypersensitivity to these agents due to unresolved DNA damage. The coordinated assembly and disassembly of BER protein complexes are essential for cell survival and for maintaining genomic integrity following alkylating agent exposure. These complexes rely on poly-ADP-ribose formation, an NAD⁺-dependent post-translational modification synthesized by PARP1 and PARP2 during the BER process. At the lesion site, poly-ADP-ribose facilitates the recruitment of XRCC1. This scaffold protein helps assemble BER proteins like DNA polymerase beta (Polβ), a bifunctional DNA polymerase containing both DNA synthesis and 5′-deoxyribose-phosphate lyase (5’dRP lyase) activity. Here, we confirm that <em>IDH1</em> mutant glioma cells have defective NAD⁺ metabolism, but still produce sufficient nuclear NAD⁺ for robust PARP1 activation and BER complex formation in response to DNA damage. However, the overproduction of 2-hydroxyglutarate, an oncometabolite produced by the IDH1 R132H mutant protein, suppresses BER capacity by reducing Polβ protein levels. This defines a novel mechanism by which the <em>IDH1</em> mutation in gliomas confers cellular sensitivity to alkylating agents and to inhibitors of the poly-ADP-ribose glycohydrolase, PARG.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"140 ","pages":"Article 103700"},"PeriodicalIF":3.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000764/pdfft?md5=fc195a6932bb7fa0a5e50e382cb46ee6&pid=1-s2.0-S1568786424000764-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141397015","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":"Broken strands, broken minds: Exploring the nexus of DNA damage and neurodegeneration","authors":"Ioanna Stavgiannoudaki ,&nbsp;Evi Goulielmaki ,&nbsp;George A. Garinis","doi":"10.1016/j.dnarep.2024.103699","DOIUrl":"10.1016/j.dnarep.2024.103699","url":null,"abstract":"<div><p>Neurodegenerative disorders are primarily characterized by neuron loss progressively leading to cognitive decline and the manifestation of incurable and debilitating conditions, such as Alzheimer's, Parkinson's, and Huntington's diseases. Loss of genome maintenance causally contributes to age-related neurodegeneration, as exemplified by the premature appearance of neurodegenerative features in a growing family of human syndromes and mice harbouring inborn defects in DNA repair. Here, we discuss the relevance of persistent DNA damage, key DNA repair mechanisms and compromised genome integrity in age-related neurodegeneration highlighting the significance of investigating these connections to pave the way for the development of rationalized intervention strategies aimed at delaying the onset of neurodegenerative disorders and promoting healthy aging.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"140 ","pages":"Article 103699"},"PeriodicalIF":3.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141274326","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 roles of TonEBP in the DNA damage response: From DNA damage bypass to R-loop resolution","authors":"Soo Youn Choi","doi":"10.1016/j.dnarep.2024.103697","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103697","url":null,"abstract":"<div><p>Tonicity-responsive enhancer binding protein (TonEBP) is a stress-responsive protein that plays a critical role in the regulation of gene expression and cellular adaptation to stressful environments. Recent studies uncovered the novel role of TonEBP in the DNA damage response, which significantly impacts genomic stability. This review provides a comprehensive overview of the novel role of TonEBP in DNA damage repair, including its involvement in the DNA damage bypass pathway and the recognition and resolution of DNA damage-induced R-loop structures.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"140 ","pages":"Article 103697"},"PeriodicalIF":3.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000739/pdfft?md5=ead9675c4f0139a27f1aa47e94138f58&pid=1-s2.0-S1568786424000739-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141325939","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":"Exploring factors influencing choice of DNA double-strand break repair pathways","authors":"Daniyar Otarbayev ,&nbsp;Kyungjae Myung","doi":"10.1016/j.dnarep.2024.103696","DOIUrl":"10.1016/j.dnarep.2024.103696","url":null,"abstract":"<div><p>DNA double-strand breaks (DSBs) represent one of the most severe threats to genomic integrity, demanding intricate repair mechanisms within eukaryotic cells. A diverse array of factors orchestrates the complex choreography of DSB signaling and repair, encompassing repair pathways, such as non-homologous end-joining, homologous recombination, and polymerase-θ-mediated end-joining. This review looks into the intricate decision-making processes guiding eukaryotic cells towards a particular repair pathway, particularly emphasizing the processing of two-ended DSBs. Furthermore, we elucidate the transformative role of Cas9, a site-specific endonuclease, in revolutionizing our comprehension of DNA DSB repair dynamics. Additionally, we explore the burgeoning potential of Cas9's remarkable ability to induce sequence-specific DSBs, offering a promising avenue for precise targeting of tumor cells. Through this comprehensive exploration, we unravel the intricate molecular mechanisms of cellular responses to DSBs, shedding light on both fundamental repair processes and cutting-edge therapeutic strategies.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"140 ","pages":"Article 103696"},"PeriodicalIF":3.8,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183679","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 dynamics and regulation of PARP1 and PARP2 in response to DNA damage and during replication","authors":"Hanwen Zhang ,&nbsp;Shan Zha","doi":"10.1016/j.dnarep.2024.103690","DOIUrl":"10.1016/j.dnarep.2024.103690","url":null,"abstract":"<div><p>DNA strand breaks activate Poly(ADP-ribose) polymerase (PARP) 1 and 2, which use NAD+ as the substrate to covalently conjugate ADP-ribose on themselves and other proteins (<em>e.g.,</em> Histone) to promote chromatin relaxation and recruit additional DNA repair factors. Enzymatic inhibitors of PARP1 and PARP2 (PARPi) are promising cancer therapy agents that selectively target BRCA1- or BRCA2- deficient cancers. As immediate early responders to DNA strand breaks with robust activities, PARP1 and PARP2 normally form transient foci (&lt;10 minutes) at the micro-irradiation-induced DNA lesions. In addition to enzymatic inhibition, PARPi also extend the presence of PARP1 and PARP2 at DNA lesions, including at replication forks, where they may post a physical block for subsequent repair and DNA replication. The dynamic nature of PARP1 and PARP2 foci made live cell imaging a unique platform to detect subtle changes and the functional interaction among PARP1, PARP2, and their regulators. Recent imaging studies have provided new understandings of the biological consequence of PARP inhibition and uncovered functional interactions between PARP1 and PARP2 and new regulators (<em>e.g.</em>, histone poly(ADP-ribosylation) factor). Here, we review recent advances in dissecting the temporal and spatial Regulation of PARP1 and PARP2 at DNA lesions and discuss their physiological implications on both cancer and normal cells.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"140 ","pages":"Article 103690"},"PeriodicalIF":3.8,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186660","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":"Functional characterization of single nucleotide polymorphic variants of DNA repair enzyme NEIL1 in South Asian populations","authors":"Jamie T. Zuckerman ,&nbsp;Asia Sage Jackson ,&nbsp;Irina G. Minko ,&nbsp;Melis Kant ,&nbsp;Pawel Jaruga ,&nbsp;Michael P. Stone ,&nbsp;Miral Dizdaroglu ,&nbsp;Amanda K. McCullough ,&nbsp;R. Stephen Lloyd","doi":"10.1016/j.dnarep.2024.103695","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103695","url":null,"abstract":"<div><p>The base excision repair (BER) pathway is a precise and versatile mechanism of DNA repair that is initiated by DNA glycosylases. Endonuclease VIII-like 1 (NEIL1) is a bifunctional glycosylase/abasic site (AP) lyase that excises a damaged base and subsequently cleaves the phosphodiester backbone. NEIL1 is able to recognize and hydrolyze a broad range of oxidatively-induced base lesions and substituted ring-fragmented guanines, including aflatoxin-induced 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B₁ (AFB₁-FapyGua). Due to NEIL1’s protective role against these and other pro-mutagenic lesions, it was hypothesized that naturally occurring single nucleotide polymorphic (SNP) variants of NEIL1 could increase human risk for aflatoxin-induced hepatocellular carcinoma (HCC). Given that populations in South Asia experience high levels of dietary aflatoxin exposures and hepatitis B viral infections that induce oxidative stress, investigations on SNP variants of NEIL1 that occur in this region may have clinical implications. In this study, the most common South Asian variants of NEIL1 were expressed, purified, and functionally characterized. All tested variants exhibited activities and substrate specificities similar to wild type (wt)-NEIL1 on high-molecular weight DNA containing an array of oxidatively-induced base lesions. On short oligodeoxynucleotides (17-mers) containing either a site-specific apurinic/apyrimidinic (AP) site, thymine glycol (ThyGly), or AFB₁-FapyGua, P206L-NEIL1 was catalytically comparable to wt-NEIL1, while the activities of NEIL1 variants Q67K and T278I on these substrates were ≈2-fold reduced. Variant T103A had a greatly diminished ability to bind to 17-mer DNAs, limiting the subsequent glycosylase and lyase reactions. Consistent with this observation, the rate of excision by T103A on 17-mer oligodeoxynucleotides containing ThyGly or AFB₁-FapyGua could not be measured. However, the ability of T103A to excise ThyGly was improved on longer oligodeoxynucleotides (51-mers), with ≈7-fold reduced activity compared to wt-NEIL1. Our studies suggest that NEIL1 variant T103A may present a pathogenic phenotype that is limited in damage recognition, potentially increasing human risk for HCC.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103695"},"PeriodicalIF":3.8,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095847","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 mutagenic consequences of defective DNA repair","authors":"Eszter Németh,&nbsp;Dávid Szüts","doi":"10.1016/j.dnarep.2024.103694","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103694","url":null,"abstract":"<div><p>Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The malfunction of distinct repair mechanisms leads to genomic instability through different mutagenic processes. For example, defective mismatch repair causes high base substitution rates and microsatellite instability, whereas homologous recombination deficiency is characteristically associated with deletions and chromosome instability. This review presents a comprehensive collection of all mutagenic phenotypes associated with the loss of each DNA repair mechanism, drawing on data from a variety of model organisms and mutagenesis assays, and placing greatest emphasis on systematic analyses of human cancer datasets. We describe the latest theories on the mechanism of each mutagenic process, often explained by reliance on an alternative repair pathway or the error-prone replication of unrepaired, damaged DNA. Aided by the concept of mutational signatures, the genomic phenotypes can be used in cancer diagnosis to identify defective DNA repair pathways.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103694"},"PeriodicalIF":3.8,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000703/pdfft?md5=f4b9d8ea21f77010d4c1947323e16e35&pid=1-s2.0-S1568786424000703-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141090079","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":"An exchange of single amino acid between the phosphohydrolase modules of Escherichia coli MutT and Mycobacterium smegmatis MutT1 switches their cleavage specificities","authors":"Elhassan Ali Fathi Emam ,&nbsp;Koyel Roy ,&nbsp;Umesh Varshney","doi":"10.1016/j.dnarep.2024.103693","DOIUrl":"10.1016/j.dnarep.2024.103693","url":null,"abstract":"<div><p>MutT proteins belong to the Nudix hydrolase superfamily that includes a diverse group of Mg²⁺ requiring enzymes. These proteins use a generalized substrate, <strong>nu</strong>cleoside <strong>di</strong>phosphate linked to a chemical group <strong>X (NDP-X</strong>), to produce nucleoside monophosphate (NMP) and the moiety X linked with phosphate (XP). <em>E. coli</em> MutT (<em>Eco</em>MutT) and mycobacterial MutT1 (<em>Msm</em>MutT1) belong to the Nudix hydrolase superfamily that utilize 8-oxo-(d)GTP (referring to both 8-oxo-GTP or 8-oxo-dGTP). However, predominant products of their activities are different. While <em>Eco</em>MutT produces 8-oxo-(d)GMP, <em>Msm</em>MutT1 gives rise to 8-oxo-(d)GDP. Here, we show that the altered cleavage specificities of the two proteins are largely a consequence of the variation at the equivalent of Gly37 (G37) in <em>Eco</em>MutT to Lys (K65) in the <em>Msm</em>MutT1. Remarkably, mutations of G37K (<em>Eco</em>MutT) and K65G (<em>Msm</em>MutT1) switch their cleavage specificities to produce 8-oxo-(d)GDP, and 8-oxo-(d)GMP, respectively. Further, a time course analysis using 8-oxo-GTP suggests that <em>Msm</em>MutT1(K65G) hydrolyses 8-oxo-(d)GTP to 8-oxo-(d)GMP in a two-step reaction via 8-oxo-(d)GDP intermediate. Expectedly, unlike <em>Eco</em>MutT (G37K) and <em>Msm</em>MutT1, <em>Eco</em>MutT and <em>Msm</em>MutT1 (K65G) rescue an <em>E. coli ΔmutT</em> strain, better by decreasing A to C mutations.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103693"},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141049690","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 role of rRNA in maintaining genome stability","authors":"Peng Li ,&nbsp;Xiaochun Yu","doi":"10.1016/j.dnarep.2024.103692","DOIUrl":"10.1016/j.dnarep.2024.103692","url":null,"abstract":"<div><p>Over the past few decades, unbiased approaches such as genetic screening and protein affinity purification have unveiled numerous proteins involved in DNA double-strand break (DSB) repair and maintaining genome stability. However, despite our knowledge of these protein factors, the underlying molecular mechanisms governing key cellular events during DSB repair remain elusive. Recent evidence has shed light on the role of non-protein factors, such as RNA, in several pivotal steps of DSB repair. In this review, we provide a comprehensive summary of these recent findings, highlighting the significance of ribosomal RNA (rRNA) as a critical mediator of DNA damage response, meiosis, and mitosis. Moreover, we discuss potential mechanisms through which rRNA may influence genome integrity.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103692"},"PeriodicalIF":3.8,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000685/pdfft?md5=cf14878fb4dbf102d1edc94574f1ef8e&pid=1-s2.0-S1568786424000685-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141054916","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":"Cdc48/p97 segregase: Spotlight on DNA-protein crosslinks","authors":"Audrey Noireterre,&nbsp;Françoise Stutz","doi":"10.1016/j.dnarep.2024.103691","DOIUrl":"https://doi.org/10.1016/j.dnarep.2024.103691","url":null,"abstract":"<div><p>The ATP-dependent molecular chaperone Cdc48 (in yeast) and its human counterpart p97 (also known as VCP), are essential for a variety of cellular processes, including the removal of DNA-protein crosslinks (DPCs) from the DNA. Growing evidence demonstrates in the last years that Cdc48/p97 is pivotal in targeting ubiquitinated and SUMOylated substrates on chromatin, thereby supporting the DNA damage response. Along with its cofactors, notably Ufd1-Npl4, Cdc48/p97 has emerged as a central player in the unfolding and processing of DPCs. This review introduces the detailed structure, mechanism and cellular functions of Cdc48/p97 with an emphasis on the current knowledge of DNA-protein crosslink repair pathways across several organisms. The review concludes by discussing the potential therapeutic relevance of targeting p97 in DPC repair.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"139 ","pages":"Article 103691"},"PeriodicalIF":3.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786424000673/pdfft?md5=c07c88cef240c56325edcd424bfa1510&pid=1-s2.0-S1568786424000673-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140918281","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}