DNA Repair最新文献

Multiple functions of PARP1 in the repair of DNA double strand breaks PARP1在DNA双链断裂修复中的多重功能

IF 3 3区生物学

DNA Repair Pub Date : 2025-07-21 DOI: 10.1016/j.dnarep.2025.103873

Raquel Ortega , Benjamin G. Bitler , Nausica Arnoult

{"title":"Multiple functions of PARP1 in the repair of DNA double strand breaks","authors":"Raquel Ortega , Benjamin G. Bitler , Nausica Arnoult","doi":"10.1016/j.dnarep.2025.103873","DOIUrl":"10.1016/j.dnarep.2025.103873","url":null,"abstract":"<div><div>Poly(ADP-ribose) polymerase 1 (PARP1) is one of the most abundant nuclear proteins in human cells and plays critical roles in numerous cellular processes, including the response to DNA damage. PARP1 is activated by and rapidly localizes to both single- and double-strand breaks, where it catalyzes the addition of poly(ADP-ribose) chains onto itself and other chromatin- or repair-associated proteins. While the role of PARP in single-strand break repair is established, its functions at double-strand breaks (DSBs) are more complex, as it can promote or inhibit various steps in the multiple pathways that repair DSBs. In this review, we examine the DSB repair contributions of PARP1, as well as those of PARP2 and PARP3, which are also activated upon damage. We discuss their influence on chromatin regulation at break sites, their role in repair pathway selection, and finally, the regulation of repair mechanisms, including homologous recombination, non-homologous end-joining, and microhomology-mediated end-joining. Understanding these diverse and sometimes opposing roles is especially important in light of the clinical use of PARP inhibitors in cancers deficient in homologous recombination repair.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103873"},"PeriodicalIF":3.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695153","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}

引用次数: 0

An economical and rapid method of comet assay and micronucleus cytome assay for genotoxicity biomonitoring using clam, Gafrarium divaricatum (Gmelin, 1791) 一种经济快速的彗星测定和微核细胞组测定法用于蛤蜊遗传毒性生物监测

IF 3 3区生物学

DNA Repair Pub Date : 2025-07-17 DOI: 10.1016/j.dnarep.2025.103870

M. Harshavarthini , Edward Inpent Campal , Shubra Singh , Nalini Poojary , Martin Xavier , Kiran D. Rasal , Madhuri S. Pathak , Naresh S. Nagpure

{"title":"An economical and rapid method of comet assay and micronucleus cytome assay for genotoxicity biomonitoring using clam, Gafrarium divaricatum (Gmelin, 1791)","authors":"M. Harshavarthini , Edward Inpent Campal , Shubra Singh , Nalini Poojary , Martin Xavier , Kiran D. Rasal , Madhuri S. Pathak , Naresh S. Nagpure","doi":"10.1016/j.dnarep.2025.103870","DOIUrl":"10.1016/j.dnarep.2025.103870","url":null,"abstract":"<div><div>The comet assay or single-cell gel electrophoresis and the micronucleus cytome assay have emerged as widely used methods for measuring DNA damage and cytotoxicity in genotoxicity testing and biomonitoring studies. The relative occurrence of micronuclei and other cellular abnormalities in dividing cells is a reliable biomarker of xenobiotic-induced genotoxicity. Bivalves are known for their bioaccumulation capabilities and are ideal bioindicators for monitoring DNA damage and chromosomal mutations. This study focuses on the optimization and standardization of genotoxicity assays, such as comet assay and micronucleus test, using forked venus clam, <em>Gafrarium divaricatum</em>, as a model organism. It highlights the potential of using cost-effective mechanical digestion method to prepare cell suspensions from clam tissues, as opposed to the more expensive enzymatic digestion techniques. It also explored the application of various staining techniques to improve the accuracy of micronucleus scoring, addressing the variability in genotoxicity assays across different laboratories. By developing a species specific standardized protocol for these assays, this investigation aimed to reduce inter-laboratory discrepancies and enhance the reliability of genotoxicity testing in marine organisms, especially in bivalves, thereby facilitating regulatory applications and environmental monitoring.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103870"},"PeriodicalIF":3.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695152","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}

引用次数: 0

Synthetic cytotoxicity profiling of cohesin mutants highlights recombination-based dependencies 内聚蛋白突变体的合成细胞毒性分析强调了基于重组的依赖性

IF 3 3区生物学

DNA Repair Pub Date : 2025-07-16 DOI: 10.1016/j.dnarep.2025.103871

Rafaela Horbach Marodin , Ecaterina Cozma , Sivan Reytan-Miron , Nigel J. O’Neil , Peter C. Stirling , Philip Hieter

{"title":"Synthetic cytotoxicity profiling of cohesin mutants highlights recombination-based dependencies","authors":"Rafaela Horbach Marodin , Ecaterina Cozma , Sivan Reytan-Miron , Nigel J. O’Neil , Peter C. Stirling , Philip Hieter","doi":"10.1016/j.dnarep.2025.103871","DOIUrl":"10.1016/j.dnarep.2025.103871","url":null,"abstract":"<div><div>Cohesin maintains genome integrity through its ability to bind and link DNA molecules via a Structural Maintenance of Chromatin (SMC) activity. These effects are manifested through its major function in sister chromatid cohesion, but also through activities during DNA replication, repair, and transcription. The array of cohesin functions can make interpreting cellular effects of cohesin loss difficult to interpret mechanistically. This is particularly important in cancer where cohesin subunit mutations are common, and where the identification of genetic dependencies would be useful for predicting the response of cohesin-mutated cells to genotoxic challenges. Here we performed a series of synthetic cytotoxicity screens with hypomorphic cohesin alleles in yeast to identify cellular pathways whose loss sensitizes cohesin-mutants to sublethal levels of genotoxic DNA damage. This dataset reveals important roles for cohesin in replication stress and homologous recombination regulation that can leave cohesin mutated cells with a dependency on translesion synthesis for survival.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103871"},"PeriodicalIF":3.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665868","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}

引用次数: 0

From cooperation to conflicts – A complicated relationship between transcription and replication 从合作到冲突——转录与复制之间的复杂关系

IF 3 3区生物学

DNA Repair Pub Date : 2025-07-16 DOI: 10.1016/j.dnarep.2025.103872

Syed Shahid Musvi , Tatiana N. Moiseeva

引用次数: 0

Transcription-coupled repair of crosslinking DNA damage 交联DNA损伤的转录偶联修复

IF 3 3区生物学

DNA Repair Pub Date : 2025-07-16 DOI: 10.1016/j.dnarep.2025.103869

Rebecca Roddan, Lucy R. Henderson, Malitha Ratnaweera, Peter J. McHugh

引用次数: 0

Unveiling cGAS mechanisms: Insights into DNA damage and immune sensing in cancer 揭示cGAS机制：对癌症中DNA损伤和免疫感知的见解

IF 3 3区生物学

DNA Repair Pub Date : 2025-07-09 DOI: 10.1016/j.dnarep.2025.103868

Min-Guk Cho , Gaorav P. Gupta

{"title":"Unveiling cGAS mechanisms: Insights into DNA damage and immune sensing in cancer","authors":"Min-Guk Cho , Gaorav P. Gupta","doi":"10.1016/j.dnarep.2025.103868","DOIUrl":"10.1016/j.dnarep.2025.103868","url":null,"abstract":"<div><div>The innate immune sensing system plays a critical role in recognizing and responding to DNA damage, which is a key factor in cancer development and progression. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, in particular, detects cytosolic double-stranded DNA (dsDNA) and activates the innate immune response. Recent studies have shown that cGAS is sequestered on chromatin by binding to the acidic patch (AP) regions of histones. Upon DNA damage, its ability to bind to chromatin-associated dsDNA fragments requires the DNA damage sensor MRE11. Upon its activation, cGAS triggers an innate immune response that can suppress tumorigenesis. However, the context-specific factors that govern whether cGAS engagement leads to effective STING pathway activation remain incompletely defined, particularly in relation to chromatin context, micronuclear integrity, and post-translational modifications. In this review, we explore the dynamic interplay between DNA damage responses and innate immune signaling through the cGAS-STING axis, with a focus on recent mechanistic advances. We further examine how cancers evade or co-opt this pathway and highlight therapeutic opportunities to exploit cGAS-STING signaling for cancer treatment.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103868"},"PeriodicalIF":3.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144655747","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}

引用次数: 0

DNA topoisomerase IIß inhibition blocks DNA end resection and synergizes with PARPi in BRCA1-deficient models 在brca1缺陷模型中，DNA拓扑异构酶isß抑制阻断DNA末端切除并与PARPi协同作用

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-27 DOI: 10.1016/j.dnarep.2025.103866

Rosa Camarillo , Rosario Prados-Carvajal , Andrés Cruz-García , Guillermo Rodríguez-Real , Andrea Herencia-Ropero , Violeta Serra , Sonia Jimeno , Pablo Huertas

{"title":"DNA topoisomerase IIß inhibition blocks DNA end resection and synergizes with PARPi in BRCA1-deficient models","authors":"Rosa Camarillo , Rosario Prados-Carvajal , Andrés Cruz-García , Guillermo Rodríguez-Real , Andrea Herencia-Ropero , Violeta Serra , Sonia Jimeno , Pablo Huertas","doi":"10.1016/j.dnarep.2025.103866","DOIUrl":"10.1016/j.dnarep.2025.103866","url":null,"abstract":"<div><div>DNA end resection is a critical step that governs how a broken chromosome will be repaired. As such, it is heavily regulated by multiple cellular signals and processes. Alterations in the regulation of DNA end resection have consequences for cell survival upon exposure to cytotoxic agents, including those used during cancer chemotherapy. Here, we identified several small molecules that affect the process of DNA end resection. Among them, we focus on determining the mode of action of merbarone, a DNA topoisomerase II inhibitor. We uncover a role of the topoisomerase IIβ isoform in the full processing of DNA breaks. Moreover, we show that the effect of merbarone is affected by the formation of G4 quadruplexes and that <em>BRCA1</em>-deficient cancer cells are sensitive to merbarone. Strikingly, this sensitivity can be partially suppressed in cell lines expressing hypomorphic versions of BRCA1 lacking exon 11, a hypomorph that has been linked to PARPi-resistance. Using cellular models, we show that PARPi- and merbarone-resistant BRCA1 exon 11 mutant cells, but not wildtype BRCA1 cells, are sensitive to the combination of both drugs. Finally, we show that combination of merbarone and the PARPi olaparib has a mild antitumor effect in a PARPi-resistant PDX model bearing a BRCA1 exon 11 mutation.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103866"},"PeriodicalIF":3.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517280","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}

引用次数: 0

FBH1 and the replication stress response: Implications for genome stability and cancer development FBH1和复制应激反应：对基因组稳定性和癌症发展的影响

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-26 DOI: 10.1016/j.dnarep.2025.103865

Joshua L. Turner, Jennifer M. Mason

引用次数: 0

PARPs and ADP-ribosyl hydrolases in cancer therapy: From drug targets to biomarkers parp和adp核苷水解酶在癌症治疗中的应用：从药物靶点到生物标志物

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-24 DOI: 10.1016/j.dnarep.2025.103863

Joséphine Groslambert , Kira Schützenhofer , Luca Palazzo , Ivan Ahel

引用次数: 0

Proofreading of mismatches within primer-template junctions by Escherichia coli DNA polymerase I in vitro and in vivo 大肠杆菌DNA聚合酶I在体外和体内对引物-模板连接错配的校正

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-23 DOI: 10.1016/j.dnarep.2025.103864

Hui-Lan Chang , Kang-Yi Su , Steven D. Goodman , Yung-Chu Chuang , Shen-Jyue Hsu , Yi-Kai Fang , Hsiao-Pei Yu , Cheng-Hao Fang , Ya-Chien Yang , Sui-Yuan Chang , Woei-horng Fang

{"title":"Proofreading of mismatches within primer-template junctions by Escherichia coli DNA polymerase I in vitro and in vivo","authors":"Hui-Lan Chang , Kang-Yi Su , Steven D. Goodman , Yung-Chu Chuang , Shen-Jyue Hsu , Yi-Kai Fang , Hsiao-Pei Yu , Cheng-Hao Fang , Ya-Chien Yang , Sui-Yuan Chang , Woei-horng Fang","doi":"10.1016/j.dnarep.2025.103864","DOIUrl":"10.1016/j.dnarep.2025.103864","url":null,"abstract":"<div><div><em>Escherichia coli</em> DNA polymerase I (Pol I) possesses a 3’ to 5’ proofreading function. Using a non-inhibitory <em>in vitro</em> proofreading assay and MALDI-TOF MS analysis, we demonstrated the Pol I proofreading function was effective at removal of mismatches within the primer-template junction. Mismatches of 1–4 nucleotides (nt) from the primer 3′ end could be completely or partially corrected, with no additional editing observed further upstream. A backward movement mechanism was proposed involving distributive backtracking of polymerase along the template to remove non-fully complemented primers in order for DNA synthesis to recover. Co-editing DNA substrates containing two mismatches, one at 1–4-nt of the primer 3’ end and the other outside of normal proofreading range, confirmed our distributive backtracking hypothesis. Additionally, a time course analysis revealed proofreading of internal mismatches was a non-processive reaction. To further confirm the validity of our proofreading model, we used <em>in vivo</em>, phagemid-derived nicked C-C substrates. Transformation results were consistent with the notion that mismatches located less than 4-nt upstream of the 3′ end could be successfully proofread. <em>In vivo</em> proofreading of double mismatches also supports our model of polymerase backtracking for internal mismatch editing.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103864"},"PeriodicalIF":3.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488960","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}

引用次数: 0