DNA Repair最新文献

{"title":"Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions","authors":"Hannah Trost ,&nbsp;Felicia Wednesday Lopezcolorado ,&nbsp;Arianna Merkell ,&nbsp;Jeremy M. Stark","doi":"10.1016/j.dnarep.2024.103791","DOIUrl":"10.1016/j.dnarep.2024.103791","url":null,"abstract":"<div><div>Repeat-mediated deletions (RMDs) are a type of deletion rearrangement that utilizes two repetitive elements to bridge a DNA double-strand break (DSB) that leads to loss of the intervening sequence and one of the repeats. Sequence divergence between repeats causes RMD suppression and indeed this divergence must be resolved in the RMD products. The mismatch repair factor, MLH1, was shown to be critical for both RMD suppression and a polarity of sequence divergence resolution in RMDs. Here, we sought to study the interrelationship between these two aspects of RMD regulation (i.e., RMD suppression and polar divergence resolution), by examining several mutants of MLH1 and its binding partner PMS2. To begin with, we show that PMS2 is also critical for both RMD suppression and polar resolution of sequence divergence in RMD products. Then, with six mutants of the MLH1-PMS2 heterodimer, we found several different patterns: three mutants showed defects in both functions, one mutant showed loss of RMD suppression but not polar divergence resolution, whereas another mutant showed the opposite, and finally one mutant showed loss of RMD suppression but had a complex effect on polar divergence resolution. These findings indicate that RMD suppression vs. polar resolution of sequence divergence are distinct functions of MLH1-PMS2.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103791"},"PeriodicalIF":3.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743342","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":"Why the ROS matters: One-electron oxidants focus DNA damage and repair on G-quadruplexes for gene regulation","authors":"Aaron M. Fleming,&nbsp;Cynthia J. Burrows","doi":"10.1016/j.dnarep.2024.103789","DOIUrl":"10.1016/j.dnarep.2024.103789","url":null,"abstract":"<div><div>Hydrogen peroxide is a precursor to reactive oxygen species (ROS) in cells because of its high reactivity with iron(II) carbonate complexes formed in the labile iron pool due to a high concentration of intracellular bicarbonate (25–100 mM). This chemistry leads to the formation of carbonate radical anion rather than hydroxyl radical, and unlike the latter ROS, CO₃^•- is a milder one-electron oxidant with high specificity for guanine oxidation in DNA and RNA. In addition to metabolism, another major source of DNA oxidation is inflammation which generates peroxynitrite, another precursor to CO₃^•- via reaction with dissolved CO₂. The identity of the ROS is important because not all radicals react with DNA in the same way. Whereas hydroxyl radical forms adducts at all four bases and reacts with multiple positions on ribose leading to base loss and strand breaks, carbonate radical anion is focused on guanosine oxidation to yield 8-oxo-7,8-dihydroguanosine in nucleic acids and the nucleotide pool, a modification that can function epigenetically in the context of a G-quadruplex. DNA sequences of multiple adjacent guanines, as found in G-quadruplex-forming sequences of gene promoters, are particularly susceptible to oxidative damage, and the focusing of CO₃^•- chemistry on these sites can lead to a transcriptional response during base excision repair. In this pathway, AP-endonuclease 1 plays a key role in accelerating G-quadruplex folding as well as recruiting activating transcription factors to impact gene expression.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103789"},"PeriodicalIF":3.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142704403","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":"PrimPol-mediated repriming elicits gap-filling by template switching and promotes cellular tolerance to cidofovir","authors":"Mubasshir Washif,&nbsp;Ryotaro Kawasumi,&nbsp;Kouji Hirota","doi":"10.1016/j.dnarep.2024.103787","DOIUrl":"10.1016/j.dnarep.2024.103787","url":null,"abstract":"<div><div>A nucleoside analog, Cidofovir (CDV), is used for the treatment of viral diseases such as cytomegalovirus retinitis and herpes virus infection. CDV converts to its active diphosphate metabolite (CDVpp) through cellular kinases and acts as a competitive inhibitor for viral polymerase thereby interfering with viral replication. However, the effect of this drug on the replication of healthy host cells and the mechanisms involved in the cellular tolerance to CDV are yet to be fully understood. In this study, we explored the mechanisms underlying cellular tolerance to CDV by screening mutant cell lines exhibiting hypersensitivity to CDV from a collection of DT40 mutants deficient in various genome maintenance systems. We identified Rad17 and PrimPol as critical factors for CDV tolerance. We found that Rad17 plays a pivotal role in activating intra-S phase checkpoint by the phosphorylation of Chk1, a vital checkpoint mediator. We showed that PrimPol, a factor involved in the release of stalled replication, plays critical roles in CDV tolerance in tandem with Rad17. We found that PrimPol deficient cells showed slower replication on the CDV-incorporated template strand than did wild-type cells, indicating a critical role of PrimPol in the continuous replication fork progression on the CDV-incorporated damaged template. PrimPol releases replication arrest with its DNA-damage bypass function and its repriming function, we thus investigated which PrimPol function is involved in CDV tolerance using the separation of function mutant genes of <em>PRIMPOL</em>. The CDV hypersensitive phenotype of PrimPol deficient cells was restored by <em>PRIMPOL</em>^Y89D (primase active / reduced polymerase activity), indicating that the repriming function of PrimPol is required for maintaining replication on the CDV-damaged template. Moreover, we found that the number of sister chromatid exchange (SCE) was reduced in PrimPol-deficient cells. These data indicate that gaps generated by PrimPol-mediated repriming on CDV-damaged templates promote post-replicative gap-filing by template switching.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103787"},"PeriodicalIF":3.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694047","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":"DNAR special issue: DNA damage responses and neurological disease The DNA damage response and neurological disease","authors":"Keith Caldecott","doi":"10.1016/j.dnarep.2024.103788","DOIUrl":"10.1016/j.dnarep.2024.103788","url":null,"abstract":"","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103788"},"PeriodicalIF":3.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683999","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 interferon response at the intersection of genome integrity and innate immunity","authors":"Filip D. Duzanic,&nbsp;Lorenza Penengo","doi":"10.1016/j.dnarep.2024.103786","DOIUrl":"10.1016/j.dnarep.2024.103786","url":null,"abstract":"<div><div>In recent years, numerous reports indicated that, besides pathogen infections, DNA replication stress and defective DNA repair can trigger the innate immune response by introducing a state of viral mimicry, due to cytosolic accumulation of the self-nucleic acid species, which culminates in the activation of type I interferon (IFN) pathway. In turn, IFN upregulates a variety of factors mutually implicated in immune- and genome-related mechanisms, shedding light on the unprecedented causality between genome stability and innate immunity. Intriguingly, in addition to being induced by replication stress, IFN-regulated factors can also promote it, pinpointing IFN signaling as both a consequence and a cause of replication stress. Here, we provide an overview of the factors and molecular mechanisms implicated in the evolutionary conserved crosstalk between genome maintenance and innate immunity, highlighting the role of the IFN-stimulated gene 15 (ISG15), which appears to be at the hub of this intersection. Moreover, we discuss the potential significance and clinical implications of the immune-mediated modulation of DNA replication and repair upon pathogen infection and in human diseases such as cancer and autoinflammatory syndromes. Finally, we discuss the relevant open questions and future directions.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"145 ","pages":"Article 103786"},"PeriodicalIF":3.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694051","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":"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":"The biochemistry of the carcinogenic alcohol metabolite acetaldehyde","authors":"Liam A. Thomas,&nbsp;Richard J. Hopkinson","doi":"10.1016/j.dnarep.2024.103782","DOIUrl":"10.1016/j.dnarep.2024.103782","url":null,"abstract":"<div><div>Acetaldehyde (AcH) is the first metabolite of ethanol and is proposed to be responsible for the genotoxic effects of alcohol consumption. As an electrophilic aldehyde, AcH can form multiple adducts with DNA and other biomolecules, leading to function-altering and potentially toxic and carcinogenic effects. In this review, we describe sources of AcH in humans, including AcH biosynthesis mechanisms, and outline the structures, properties and functions of AcH-derived adducts with biomolecules. We also describe human AcH detoxification mechanisms and discuss ongoing challenges in the field.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"144 ","pages":"Article 103782"},"PeriodicalIF":3.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683997","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":"One-ended and two-ended breaks at nickase-broken replication forks","authors":"Ralph Scully ,&nbsp;Johannes C. Walter ,&nbsp;André Nussenzweig","doi":"10.1016/j.dnarep.2024.103783","DOIUrl":"10.1016/j.dnarep.2024.103783","url":null,"abstract":"<div><div>Replisome collision with a nicked parental DNA template can lead to the formation of a replication-associated double strand break (DSB). How this break is repaired has implications for cancer initiation, cancer therapy and therapeutic gene editing. Recent work shows that collision of a replisome with a nicked DNA template can give rise to either a single-ended (se) or a double-ended (de)DSB, with potentially divergent effects on repair pathway choice and genomic instability. Emerging evidence suggests that the biochemical environment of the broken mammalian replication fork may be specialized in such a way as to skew repair in favor of homologous recombination at the expense of non-homologous end joining.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"144 ","pages":"Article 103783"},"PeriodicalIF":3.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587375","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}