DNA Repair最新文献

{"title":"Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond","authors":"Hayley L. Rein ,&nbsp;Kara A. Bernstein","doi":"10.1016/j.dnarep.2023.103563","DOIUrl":"10.1016/j.dnarep.2023.103563","url":null,"abstract":"<div><p><span><span>For many individuals harboring a variant of uncertain functional significance (VUS) in a homologous recombination (HR) gene, their risk of developing breast and </span>ovarian cancer is unknown. Integral to the process of HR are </span><span><em>BRCA1</em></span><span> and regulators of the central HR protein, RAD51, including </span><span><em>BRCA2</em><span><em>, </em><em>PALB2</em><span><em>, </em><em>RAD51C</em></span></span></span> and <em>RAD51D</em><span>. Due to advancements in sequencing technology and the continued expansion of cancer screening panels, the number of VUS identified in these genes has risen significantly. Standard practices for variant classification utilize different types of predictive, population, phenotypic, allelic and functional evidence. While variant analysis is improving, there remains a struggle to keep up with demand. Understanding the effects of an HR variant can aid in preventative care and is critical for developing an effective cancer treatment plan. In this review, we discuss current perspectives in the classification of variants in the breast and ovarian cancer genes </span><em>BRCA1, BRCA2, PALB2, RAD51C</em> and <em>RAD51D</em>.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"130 ","pages":"Article 103563"},"PeriodicalIF":3.8,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10128887","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":"Centromere: A Trojan horse for genome stability","authors":"Andrea Scelfo,&nbsp;Daniele Fachinetti","doi":"10.1016/j.dnarep.2023.103569","DOIUrl":"10.1016/j.dnarep.2023.103569","url":null,"abstract":"<div><p>Centromeres<span> play a key role in the maintenance of genome stability to prevent carcinogenesis and diseases. They are specialized chromosome loci essential to ensure faithful transmission of genomic information across cell generations by mediating the interaction with spindle microtubules. Nonetheless, while fulfilling these essential roles, their distinct repetitive composition and susceptibility to mechanical stresses during cell division render them susceptible to breakage events. In this review, we delve into the present understanding of the underlying causes of centromere fragility, from the mechanisms governing its DNA replication and repair, to the pathways acting to counteract potential challenges. We propose that the centromere represents a “Trojan horse” exerting vital functions that, at the same time, potentially threatens whole genome stability.</span></p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"130 ","pages":"Article 103569"},"PeriodicalIF":3.8,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10590180","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":"Mechanistic insights from high resolution DNA damage analysis to understand mixed radiation exposure","authors":"Pamela Akuwudike ,&nbsp;Milagrosa López-Riego ,&nbsp;Józef Ginter ,&nbsp;Lei Cheng ,&nbsp;Anna Wieczorek ,&nbsp;Katarzyna Życieńska ,&nbsp;Małgorzata Łysek-Gładysińska ,&nbsp;Andrzej Wojcik ,&nbsp;Beata Brzozowska ,&nbsp;Lovisa Lundholm","doi":"10.1016/j.dnarep.2023.103554","DOIUrl":"10.1016/j.dnarep.2023.103554","url":null,"abstract":"<div><p>Cells exposed to densely ionising high and scattered low linear energy transfer (LET) radiation (50 % dose of each) react more strongly than to the same dose of each separately. The relationship between DNA double strand break location inside the nucleus and chromatin structure was evaluated, using high-resolution transmission electron microscopy (TEM) in breast cancer MDA-MB-231 cells at 30 min post 5 Gy. Additionally, response to high and/or low LET radiation was assessed using single (1 ×1.5 Gy) versus fractionated dose delivery (5 ×0.3 Gy). By TEM analysis, the highest total number of γH2AX nanobeads were found in cells irradiated with alpha radiation just prior to gamma radiation (called mixed beam), followed by alpha, then gamma radiation. γH2AX foci induced by mixed beam radiation tended to be surrounded by open chromatin (lighter TEM regions), yet foci containing the highest number of beads, i.e. larger foci representing complex damage, remained in the heterochromatic areas. The γH2AX large focus area was also greater in mixed beam-treated cells when analysed by immunofluorescence. Fractionated mixed beams given daily induced the strongest reduction in cell viability and colony formation in MDA-MB-231 and osteosarcoma U2OS cells compared to the other radiation qualities, as well as versus acute exposure. This may partially be explained by recurring low LET oxidative DNA damage by every fraction together with a delay in recompaction of chromatin after high LET, demonstrated by low levels of heterochromatin marker H3K9me3 at 2 h after the last mixed beam fraction in MDA-MB-231. In conclusion, early differences in response to complex DNA damage may lead to a stronger cell kill induced by fractionated exposure, which suggest a therapeutic potential of combined high and low LET irradiation.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"130 ","pages":"Article 103554"},"PeriodicalIF":3.8,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786423001088/pdfft?md5=c7058cb58abd9fed86bfa6fb48e60d29&pid=1-s2.0-S1568786423001088-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10016587","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":"Metazoan nuclear pore complexes in gene regulation and genome stability","authors":"Parisa Nobari ,&nbsp;Valérie Doye ,&nbsp;Charlene Boumendil","doi":"10.1016/j.dnarep.2023.103565","DOIUrl":"10.1016/j.dnarep.2023.103565","url":null,"abstract":"<div><p>The nuclear pore complexes (NPCs), one of the hallmarks of eukaryotic nuclei, allow selective transport of macromolecules between the cytoplasm and the nucleus. Besides this canonical function, an increasing number of additional roles have been attributed to the NPCs and their constituents, the nucleoporins. Here we review recent insights into the mechanisms by which NPCs and nucleoporins affect transcription and DNA repair in metazoans. In the first part, we discuss how gene expression can be affected by the localization of genome-nucleoporin interactions at pores or “off-pores”, by the role of nucleoporins in chromatin organization at different scales, or by the physical properties of nucleoporins. In the second part, we review the contribution of NPCs to genome stability, including transport-dependent and -independent functions and the role of positioning at NPCs in the repair of heterochromatic breaks and the regulation of replication stress.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"130 ","pages":"Article 103565"},"PeriodicalIF":3.8,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1568786423001192/pdfft?md5=5457c19a48ad70ad4d919c12c5d0df35&pid=1-s2.0-S1568786423001192-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10212883","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":"Multi-scale cellular imaging of DNA double strand break repair","authors":"Tim Heemskerk ,&nbsp;Gerarda van de Kamp ,&nbsp;Jeroen Essers ,&nbsp;Roland Kanaar ,&nbsp;Maarten W. Paul","doi":"10.1016/j.dnarep.2023.103570","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103570","url":null,"abstract":"<div><p>Live-cell and high-resolution fluorescence microscopy are powerful tools to study the organization and dynamics of DNA double-strand break repair foci and specific repair proteins in single cells. This requires specific induction of DNA double-strand breaks and fluorescent markers to follow the DNA lesions in living cells. In this review, where we focused on mammalian cell studies, we discuss different methods to induce DNA double-strand breaks, how to visualize and quantify repair foci in living cells., We describe different (live-cell) imaging modalities that can reveal details of the DNA double-strand break repair process across multiple time and spatial scales. In addition, recent developments are discussed in super-resolution imaging and single-molecule tracking, and how these technologies can be applied to elucidate details on structural compositions or dynamics of DNA double-strand break repair.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"131 ","pages":"Article 103570"},"PeriodicalIF":3.8,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24849378","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":"Chromatin meets the cytoskeleton: the importance of nuclear actin dynamics and associated motors for genome stability","authors":"Hans-Peter Wollscheid,&nbsp;Helle D. Ulrich","doi":"10.1016/j.dnarep.2023.103571","DOIUrl":"https://doi.org/10.1016/j.dnarep.2023.103571","url":null,"abstract":"<div><p>The actin cytoskeleton is of fundamental importance for numerous cellular processes, including intracellular transport, cell plasticity, and cell migration. However, functions of filamentous actin (F-actin) in the nucleus remain understudied due to the comparatively low abundance of nuclear actin and the resulting experimental limitations to its visualization. Owing to recent technological advances such as super-resolution microscopy and the development of nuclear-specific actin probes, essential roles of the actin cytoskeleton in the context of genome maintenance are now emerging. In addition to the contributions of monomeric actin as a component of multiple important nuclear protein complexes, nuclear actin has been found to undergo polymerization in response to DNA damage and DNA replication stress. Consequently, nuclear F-actin plays important roles in the regulation of intra-nuclear mobility of repair and replication foci as well as the maintenance of nuclear shape, two important aspects of efficient stress tolerance. Beyond actin itself, there is accumulating evidence for the participation of multiple actin-binding proteins (ABPs) in the surveillance of genome integrity, including nucleation factors and motor proteins of the myosin family. Here we summarize recent findings highlighting the importance of actin cytoskeletal factors within the nucleus in key genome maintenance pathways.</p></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"131 ","pages":"Article 103571"},"PeriodicalIF":3.8,"publicationDate":"2023-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24849382","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":"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}