DNA Repair最新文献

{"title":"Intersection of the fragile X-related disorders and the DNA damage response","authors":"Daman Kumari ,&nbsp;Jessalyn Grant-Bier ,&nbsp;Farid Kadyrov ,&nbsp;Karen Usdin","doi":"10.1016/j.dnarep.2024.103785","DOIUrl":"10.1016/j.dnarep.2024.103785","url":null,"abstract":"<div><div>The Repeat Expansion Diseases (REDs) are a large group of human genetic disorders that result from an increase in the number of repeats in a disease-specific tandem repeat or microsatellite. Emerging evidence suggests that the repeats trigger an error-prone form of DNA repair that causes the expansion mutation by exploiting a limitation in normal mismatch repair. Furthermore, while much remains to be understood about how the mutation causes pathology in different diseases in this group, there is evidence to suggest that some of the downstream consequences of repeat expansion trigger the DNA damage response in ways that contribute to disease pathology. This review will discuss these subjects in the context of the Fragile X-related disorders (aka the <em>FMR1</em> disorders) that provide a particularly interesting example of the intersection between the repeats and the DNA damage response that may also be relevant for many other diseases in this group.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"144 ","pages":"Article 103785"},"PeriodicalIF":3.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644799","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":"Discovery of KPT-6566 as STAG1/2 Inhibitor sensitizing PARP and NHEJ Inhibitors to suppress tumor cells growth in vitro","authors":"Qinwei Zhu,&nbsp;Xuening Chen,&nbsp;Zhonghui Lin","doi":"10.1016/j.dnarep.2024.103784","DOIUrl":"10.1016/j.dnarep.2024.103784","url":null,"abstract":"<div><div>Stromal antigen 1 and 2 (STAG1 and STAG2) are two mutually exclusive components of the cohesin complex that is crucial for centromeric and telomeric cohesion. Beyond its structural role, STAG2 also plays a pivotal role in homologous recombination (HR) repair and has emerged as a promising therapeutic target in cancer treatment. Here, we employed a fluorescence polarization (FP)-based high-throughput screening and identified KPT-6566 as a dual inhibitor of STAG1 and STAG2. Biochemical and biophysical analyses demonstrated that KPT-6566 directly binds to STAG1 and STAG2, disrupting their interactions with SCC1 and double-stranded DNA. A metaphase chromosome spread assay showed that KPT-6566 causes premature chromosome separation and induces chromosome damages in HeLa cells. Furthermore, KPT-6566 also impairs DNA damage repair, leading to the accumulation of double-strand breaks and cell apoptosis. Finally, KPT-6566 can sensitize HeLa and HepG2 cells to PARP inhibitor Olaparib and the NHEJ inhibitor UMI-77, exhibiting a synergistic effect in suppressing cell proliferation. Our findings highlight the potential of STAG1/2 as promising therapeutic targets in cancer treatment, particularly when they are targeted in combination with other DNA damage response inhibitors.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"144 ","pages":"Article 103784"},"PeriodicalIF":3.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634202","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":"Transient HR enhancement by RAD51-stimulatory compound confers protection on intestinal rather than hematopoietic tissue against irradiation in mice","authors":"Zhiyu Lu ,&nbsp;Dong Chen ,&nbsp;Ning Zhang ,&nbsp;Zhiyuan Zheng ,&nbsp;Zimo Zhou ,&nbsp;Guochen Liu ,&nbsp;Jiawei An ,&nbsp;Yong Wang ,&nbsp;Yongping Su ,&nbsp;Wensheng Chen ,&nbsp;Fengchao Wang","doi":"10.1016/j.dnarep.2024.103781","DOIUrl":"10.1016/j.dnarep.2024.103781","url":null,"abstract":"<div><div>DNA double-strand breaks (DSBs) are cytotoxic lesions that compromise genomic integrity and trigger cell death. Homologous recombination (HR) is a major pathway for repairing DSBs in cycling cells. However, it remains unclear whether transient modulation of HR could confer protection to adult stem cells against lethal irradiation exposure. In this study, we investigated the radio-protective effect of the RAD51-stimulatory compound RS-1 on adult stem cells and progenitor cells with varying cycling rates in intestinal and hematopoietic tissues. Treatment with RS-1 even at high doses did not induce noticeable cell death or proliferation of intestinal crypt cells in vivo. Pretreatment with RS-1 before irradiation significantly decreased mitotic death, promoted DNA repair and enhanced the survival of intestinal stem cells and progenitor cells and increased the number of regenerative crypt colonies thereby mitigating IR-induced gastrointestinal syndrome. Moreover, RS-1 pretreatment could increase the survival and regeneration of irradiated intestinal organoids in vitro, which can be rescued by RAD51 inhibitor. However, pretreatment with RS-1 in vivo did not elevate nucleated cell count or HSPCs in bone marrow after 6 Gy irradiation. Additionally, there was no impact on mouse survival due to drug treatment observed. Thus, our data suggest that targeting HR as a strategy to prevent tissue damage from acute irradiation exposure may depend on cell cycling rates and intrinsic DNA repair mechanisms.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"144 ","pages":"Article 103781"},"PeriodicalIF":3.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634368","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":"Spatio-temporal dynamics of the DNA glycosylase OGG1 in finding and processing 8-oxoguanine","authors":"Luana Cintori ,&nbsp;Anne-Marie Di Guilmi ,&nbsp;Yvan Canitrot ,&nbsp;Sebastien Huet ,&nbsp;Anna Campalans","doi":"10.1016/j.dnarep.2023.103550","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103550","url":null,"abstract":"<div><p>OGG1 is the DNA glycosylase responsible for the removal of the oxidative lesion 8-oxoguanine (8-oxoG) from DNA. The recognition of this lesion by OGG1 is a complex process that involves scanning the DNA for the presence of 8-oxoG, followed by recognition and lesion removal. Structural data have shown that OGG1 evolves through different stages of conformation onto the DNA, corresponding to elementary steps of the 8-oxoG recognition and extrusion from the double helix. Single-molecule studies of OGG1 on naked DNA have shown that OGG1 slides in persistent contact with the DNA, displaying different binding states probably corresponding to the different conformation stages. However, in cells, the DNA is not naked and OGG1 has to navigate into a complex and highly crowded environment within the nucleus. To ensure rapid detection of 8-oxoG, OGG1 alternates between 3D diffusion and sliding along the DNA. This process is regulated by the local chromatin state but also by protein co-factors that could facilitate the detection of oxidized lesions. We will review here the different methods that have been used over the last years to better understand how OGG1 detects and process 8-oxoG lesions.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"129 ","pages":"Article 103550"},"PeriodicalIF":3.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3455390","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":"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":"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":"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":"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}