DNA Repair最新文献

{"title":"Evolution of the triplet BRCT domain","authors":"M.B.S. Mota ,&nbsp;N.T. Woods ,&nbsp;M.A. Carvalho ,&nbsp;A.N.A. Monteiro ,&nbsp;R.D. Mesquita","doi":"10.1016/j.dnarep.2023.103532","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103532","url":null,"abstract":"<div><p><span>Organisms have evolved a complex system, called the DNA damage response<span><span> (DDR), which maintains genome integrity. The DDR is responsible for identifying and repairing a variety of lesions and alterations in DNA. DDR proteins coordinate DNA damage detection, </span>cell cycle arrest<span>, and repair, with many of these events regulated by protein phosphorylation. In the human </span></span></span>proteome<span><span>, 23 proteins contain the BRCT (BRCA1 C‐Terminus domain) domain, a modular signaling domain that can bind phosphopeptides and mediate protein-protein interactions. BRCTs can be found as functional single units, tandem (tBRCT), triplet (tpBRCT), and quartet. Here we examine the evolution of the tpBRCT architecture present in TOPBP1 (DNA topoisomerase II binding protein 1) and ECT2 (epithelial cell transforming 2), and their respective interaction partners RAD9 (Cell cycle checkpoint control protein RAD9) and CYK-4 (Rac GTPase-activating protein 1), with a focus on the conservation of the phosphopeptide-binding residues. The pair TOPBP1-RAD9 arose with the Eukaryotes and ECT2-CYK-4 with the Eumetazoans. Triplet structural and functional characteristics were conserved in almost all organisms. The first unit of the triplet (BRCT0) is different from the other two BRCTs but conserved between orthologs for both TOPBP1 and ECT2. BRCT domain evolution simulations suggest a trend to retain the singlet or towards two or three BRCT copies per protein consistent with functional tBRCT and tpBRCT architectures. Our results shed light on the emergence of the function and architecture of multiple BRCT domain organizations and provide information about the evolution of the BRCT triplet. Knowledge of BRCT domain evolution can improve the understanding of DNA damage response mechanisms and </span>signal transduction in DDR.</span></p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103532"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3081565","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 non-productive complexes of DNA repair proteins with DNA lesions","authors":"Ingrid Tessmer","doi":"10.1016/j.dnarep.2023.103542","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103542","url":null,"abstract":"<div><p><span><span><span><span>A multitude of different types of lesions is continuously introduced into the DNA inside our cells, and their rapid and efficient repair is fundamentally important for the maintenance of </span>genomic stability and </span>cellular viability<span>. This is achieved by a number of DNA repair systems that each involve different protein factors and employ versatile strategies to target different types of DNA lesions. Intriguingly, specialized DNA repair proteins have also evolved to form non-functional complexes with their target lesions. These proteins allow the marking of innocuous lesions to render them visible for DNA repair systems and can serve to directly recruit DNA repair cascades. Moreover, they also provide links between different DNA repair mechanisms or even between DNA lesions and </span></span>transcription regulation<span><span>. I will focus here in particular on recent findings from single molecule analyses on the alkyltransferase-like protein ATL, which is believed to initiate nucleotide excision repair (NER) of non-native NER target lesions, and the </span>base excision repair (BER) enzyme </span></span>hOGG1<span><span>, which recruits the oncogene<span> transcription factor Myc to gene promoters under </span></span>oxidative stress.</span></p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103542"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1566404","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 analyses of single nucleotide polymorphic variants of the DNA glycosylase NEIL1 in sub-Saharan African populations","authors":"Jamie T. Zuckerman ,&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.2023.103544","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103544","url":null,"abstract":"<div><p>Nei-like glycosylase 1 (NEIL1) is a DNA repair enzyme that initiates the base excision repair (BER) pathway to cleanse the human genome of damage. The substrate specificity of NEIL1 includes several common base modifications formed under oxidative stress conditions, as well as the imidazole ring open adducts that are induced by alkylating agents following initial modification at N7 guanine. An example of the latter is the persistent and mutagenic 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B₁ (AFB₁-FapyGua) adduct, resulting from the alkylating agent aflatoxin B₁ (AFB₁) <em>exo</em>-8–9-epoxide. Naturally occurring single nucleotide polymorphic (SNP) variants of NEIL1 are hypothesized to be associated with an increased risk for development of early-onset hepatocellular carcinoma (HCC), especially in environments with high exposures to aflatoxins and chronic inflammation from viral infections and alcohol consumption. Given that AFB₁ exposures and hepatitis B viral (HBV) infections represent a major problem in the developing countries of sub-Saharan Africa, it is pertinent to study SNP NEIL1 variants that are present in this geographic region. In this investigation, we characterized the three most common NEIL1 variants found in this region: P321A, R323G, and I182M. Biochemical analyses were conducted to determine the proficiencies of these variants in initiating the repair of DNA lesions. Our data show that damage recognition and excision activities of P321A and R323G were near that of wild-type (WT) NEIL1 for both thymine glycol (ThyGly) and AFB₁-FapyGua. The substrate specificities of these variants with respect to various oxidatively-induced base lesions were also similar to that of WT. In contrast, the I182M variant was unstable, such that it precipitated under a variety of conditions and underwent rapid inactivation at a biologically relevant temperature, with partial stabilization being observed in the presence of undamaged DNA. This study provides insight regarding the potential increased risk for early-onset HCC in human populations carrying the NEIL1 I182M variant.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103544"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3455389","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":"Impairment of the non-catalytic subunit Dpb2 of DNA Pol ɛ results in increased involvement of Pol δ on the leading strand","authors":"Michal Dmowski ,&nbsp;Karolina Makiela-Dzbenska ,&nbsp;Sushma Sharma ,&nbsp;Andrei Chabes ,&nbsp;Iwona J. Fijalkowska","doi":"10.1016/j.dnarep.2023.103541","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103541","url":null,"abstract":"<div><p>The generally accepted model assumes that leading strand synthesis is performed by Pol ε, while lagging-strand synthesis is catalyzed by Pol δ. Pol ε has been shown to target the leading strand by interacting with the CMG helicase [Cdc45 Mcm2–7 GINS(Psf1–3, Sld5)]. Proper functioning of the CMG-Pol ɛ, the helicase-polymerase complex is essential for its progression and the fidelity of DNA replication. Dpb2p, the essential non-catalytic subunit of Pol ε plays a key role in maintaining the correct architecture of the replisome by acting as a link between Pol ε and the CMG complex. Using a temperature-sensitive <em>dpb2–100</em> mutant previously isolated in our laboratory, and a genetic system which takes advantage of a distinct mutational signature of the Pol δ-L612M variant which allows detection of the involvement of Pol δ in the replication of particular DNA strands we show that in yeast cells with an impaired Dpb2 subunit, the contribution of Pol δ to the replication of the leading strand is significantly increased.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103541"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2378468","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":"Clinical evidence for a role of E2F1-induced replication stress in modulating tumor mutational burden and immune microenvironment","authors":"Ke Tan ,&nbsp;Yizhe Song ,&nbsp;Min Xu ,&nbsp;Zhongsheng You","doi":"10.1016/j.dnarep.2023.103531","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103531","url":null,"abstract":"<div><p><span><span><span><span>DNA replication stress (RS) is frequently induced by </span>oncogene activation and is believed to promote tumorigenesis. However, clinical evidence for the role of oncogene-induced RS in tumorigenesis remains scarce, and the mechanisms by which RS promotes cancer development remain incompletely understood. By performing a series of bioinformatic analyses on the oncogene </span>E2F1<span>, other RS-inducing factors, and replication fork processing factors in TCGA cancer database using previously established tools, we show that hyperactivity of E2F1 likely promotes the expression of several of these factors in virtually all types of cancer to induce RS and cytosolic self-DNA production. In addition, the expression of these factors positively correlates with that of ATR and Chk1 that govern the cellular response to RS, the tumor mutational load, and tumor </span></span>infiltration of immune-suppressive CD4</span>⁺<span>Th2 cells and myeloid-derived suppressor cells (MDSCs). Consistently, high expression of these factors is associated with poor patient survival. Our study provides new insights into the role of E2F1-induced RS in tumorigenesis and suggests therapeutic approaches for E2F1-overexpressing cancers by targeting genomic instability, cytosolic self-DNA and the tumor immune microenvironment.</span></p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103531"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1566403","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 approaches for DNA damage detection and repair: A focus on Repair Assisted Damage Detection (RADD)","authors":"Tahir Detinis Zur,&nbsp;Jasline Deek,&nbsp;Yuval Ebenstein","doi":"10.1016/j.dnarep.2023.103533","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103533","url":null,"abstract":"<div><p>The human genome is continually exposed to various stressors, which can result in DNA damage, mutations, and diseases. Among the different types of DNA damage, single-strand lesions are commonly induced by external stressors and metabolic processes. Accurate detection and quantification of DNA damage are crucial for understanding repair mechanisms, assessing environmental impacts, and evaluating response to therapy. However, traditional techniques have limitations in sensitivity and the ability to detect multiple types of damage. In recent years, single-molecule fluorescence approaches have emerged as powerful tools for precisely localizing and quantifying DNA damage. Repair Assisted Damage Detection (RADD) is a single-molecule technique that employs specific repair enzymes to excise damaged bases and incorporates fluorescently labeled nucleotides to visualize the damage. This technique provides valuable insights into repair efficiency and sequence-specific damage. In this review, we discuss the principles and applications of RADD assays, highlighting their potential for enhancing our understanding of DNA damage and repair processes.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103533"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10496029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3081566","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 analysis of protein recruitment to laser microirradiation-induced DNA damage in live cells: Best practices for data analysis","authors":"Ryan M. Bianchini,&nbsp;Ebba U. Kurz","doi":"10.1016/j.dnarep.2023.103545","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103545","url":null,"abstract":"<div><p>Laser microirradiation coupled with live-cell fluorescence microscopy<span> is a powerful technique that has been used widely in studying the recruitment and retention of proteins at sites of DNA damage. Results obtained from this technique can be found in published works by both seasoned and infrequent users of microscopy. However, like many other microscopy-based techniques, the presentation of data from laser microirradiation experiments is inconsistent; papers report a wide assortment of analytic techniques, not all of which result in accurate and/or appropriate representation of the data. In addition to the varied methods of analysis, experimental and analytical details are commonly under-reported. Consequently, publications reporting data from laser microirradiation coupled with fluorescence microscopy experiments need to be carefully and critically assessed by readers. Here, we undertake a systematic investigation of commonly reported corrections used in the analysis of laser microirradiation data. We validate the critical need to correct data for photobleaching and we identify key experimental parameters that must be accounted for when presenting data from laser microirradiation experiments. Furthermore, we propose a straightforward, four-step analytical protocol that can readily be applied across platforms and that aims to improve the quality of data reporting in the DNA damage field.</span></p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103545"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2378469","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 multifaceted functions of homologous recombination in dealing with replication-associated DNA damages","authors":"Shrena Chakraborty ,&nbsp;Kamila Schirmeisen ,&nbsp;Sarah AE Lambert","doi":"10.1016/j.dnarep.2023.103548","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103548","url":null,"abstract":"<div><p>The perturbation of DNA replication, a phenomena termed “replication stress”, is a driving force of genome instability and a hallmark of cancer cells. Among the DNA repair mechanisms that contribute to tolerating replication stress, the homologous recombination pathway is central to the alteration of replication fork progression. In many organisms, defects in the homologous recombination machinery result in increased cell sensitivity to replication-blocking agents and a higher risk of cancer in humans. Moreover, the status of homologous recombination in cancer cells often correlates with the efficacy of anti-cancer treatment. In this review, we discuss our current understanding of the different functions of homologous recombination in fixing replication-associated DNA damage and contributing to complete genome duplication. We also examine which functions are pivotal in preventing cancer and genome instability.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103548"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2378470","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":"Frailty, sex, and poverty are associated with DNA damage and repair in frail, middle-aged urban adults","authors":"Jessica T. Smith ,&nbsp;Nicole Noren Hooten ,&nbsp;Nicolle A. Mode ,&nbsp;Alan B. Zonderman ,&nbsp;Ngozi Ezike ,&nbsp;Simran Kaushal ,&nbsp;Michele K. Evans","doi":"10.1016/j.dnarep.2023.103530","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103530","url":null,"abstract":"<div><p>Frailty is an age-related syndrome characterized by reduced recovery from stressors and increased risks of morbidity and mortality. Although frailty is usually studied in those over 65 years, our previous work showed that frailty is both present and a risk factor for premature mortality in midlife. We identified altered gene expression patterns and biological pathways associated with inflammation in frailty. Evidence suggests DNA oxidation damage related to inflammation accumulates with age, and that DNA repair capacity (DRC) declines with age and age-related conditions. We hypothesized that inter-individual differences in DNA oxidation damage and DRC are associated with frailty status and poverty level. Using the CometChip assay, we assessed baseline single-strand breaks and hydrogen peroxide (H₂O₂)-induced DNA oxidation damage and DRC in non-frail and frail middle-aged African American and White individuals with household incomes above and below poverty. Analysis of baseline single-strand breaks showed no associations with frailty, poverty, race, or sex. However, we identified an interaction between frailty and poverty in H₂O₂-induced DNA oxidation damage. We also identified interactions between sex and frailty as well as sex and poverty status with DRC. The social determinant of health, poverty, associates with DRC in men. Baseline DNA damage, H₂O₂-induced DNA damage as well as DRC were associated with serum cytokine levels. IL-10 levels were inversely associated with baseline DNA damage as well as H₂O₂-induced DNA damage, DRC was altered by IL-4 levels and sex, and by TNF-α levels in the context of sex and poverty status. This is the first evidence that DRC may be influenced by poverty status at midlife. Our data show that social determinants of health should be considered in examining biological pathways through which disparate age-related health outcomes become manifest.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103530"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1566402","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":"Phosphoregulation of the checkpoint kinase Mec1ATR","authors":"Luke A. Yates ,&nbsp;Xiaodong Zhang","doi":"10.1016/j.dnarep.2023.103543","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103543","url":null,"abstract":"<div><p>Yeast Mec1, and its mammalian ortholog, Ataxia-Telangiectasia and Rad3-related, are giant protein kinases central to replication stress and double strand DNA break repair. Mec1^ATR, in complex with Ddc2^ATRIP, is a ‘sensor’ of single stranded DNA, and phosphorylates numerous cell cycle and DNA repair factors to enforce cell cycle arrest and facilitate repair. Over the last several years, new techniques — particularly in structural biology — have provided molecular mechanisms for Mec1^ATR function. It is becoming increasingly clear how post-translational modification of Mec1^ATR and its interaction partners modulates the DNA damage checkpoint. In this review, we summarise the most recent work unravelling Mec1^ATR function in the DNA damage checkpoint and provide a molecular context for its regulation by phosphorylation.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103543"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2892182","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}