DNA Repair最新文献_第5页

DNA damage response inhibitors in cancer therapy: Mechanisms, clinical development, and combination strategies DNA损伤反应抑制剂在癌症治疗中的应用：机制、临床发展和联合策略

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-09-01 Epub Date: 2025-08-21 DOI: 10.1016/j.dnarep.2025.103887

Seon-gyeong Lee , Jinwoo Kim , Euihwan Jeong , Kyungjae Myung

{"title":"DNA damage response inhibitors in cancer therapy: Mechanisms, clinical development, and combination strategies","authors":"Seon-gyeong Lee , Jinwoo Kim , Euihwan Jeong , Kyungjae Myung","doi":"10.1016/j.dnarep.2025.103887","DOIUrl":"10.1016/j.dnarep.2025.103887","url":null,"abstract":"<div><div>Impaired genomic stability is a hallmark of many cancers, with the DNA damage response (DDR) mechanisms serving as critical safeguards for maintaining genomic integrity. These intricate DDR networks, encompassing various DNA repair and damage checkpoint pathways, are essential for regulating the cell cycle, immune responses, and apoptosis. Notably, defects in DDR pathways, particularly those involving BRCA1/2 mutations, present exploitable vulnerabilities for targeted therapies such as PARP inhibitors (PARPi). This review explores the mechanisms by which PARPi function as cancer therapies, focusing on their ability to inhibit DNA repair processes and induce tumor cell death. It also examines the current landscape of PARPi clinical trials and their application across various cancer types. In addition, we discuss emerging DDR inhibitors, including CHK1/2, ATR, ATM, RAD51, APE1, and WEE1, many of which act by inhibiting DNA repair and damage checkpoints. These inhibitors selectively target malignant cells that are deficient in checkpoint function, thereby inducing replication stress and mitotic catastrophe. While DDR inhibitors hold great potential as standalone therapies or in combination with chemotherapy, immunotherapy, and radiation, challenges persist, including overlapping toxicities and damage to healthy tissues. This review aims to illuminate the rapidly advancing field of DDR-based targeted cancer therapies, emphasizing their potential to revolutionize treatment approaches and improve patient outcomes.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103887"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895334","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

Contributions of DNA double strand break repair pathways to DNA crosslink repair DNA双链断裂修复途径对DNA交联修复的贡献

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-09-01 Epub Date: 2025-08-30 DOI: 10.1016/j.dnarep.2025.103889

Gerarda van de Kamp , Israel Tojal da Silva , Sander Barnhoorn , Roland Kanaar , Jeroen Essers

{"title":"Contributions of DNA double strand break repair pathways to DNA crosslink repair","authors":"Gerarda van de Kamp , Israel Tojal da Silva , Sander Barnhoorn , Roland Kanaar , Jeroen Essers","doi":"10.1016/j.dnarep.2025.103889","DOIUrl":"10.1016/j.dnarep.2025.103889","url":null,"abstract":"<div><div>DNA crosslink-inducing drugs are widely used in clinical settings for treatment of solid tumors. Double strand breaks (DSBs) that arise during interstrand crosslink (ICL) repair are crucial determinants of the therapeutic response, as they lead to cell death if not repaired. DSBs can be repaired through non-homologous end joining (NHEJ), theta-mediated end joining (TMEJ), and homologous recombination (HR). HR is considered a major pathway for repairing DSBs induced during ICL repair. In this study, we examine the roles of NHEJ, TMEJ, and HR in ICL repair using mouse embryonic stem (mES) cells. We show that DNA-PK<sub>cs</sub>-deficient mES cells are resistant to the crosslinkers mitomycin C (MMC), cisplatin and carboplatin, contrasting with the increased sensitivity observed in mES cells lacking Rad54. Furthermore, the absence of DNA-PK<sub>cs</sub> correlates with enhanced HR activity, as evidenced by an increased number of Rad54 foci following MMC treatment. The combined knock-outof DNA-PK<sub>cs</sub> and Rad54 reduces sensitivity to crosslinkers compared to cells lacking only Rad54, suggesting the involvement of another DSB repair pathway besides HR. We found that TMEJ deficiency can sensitize cells to cisplatin, particularly in those lacking NHEJ and HR repair. This suggests that TMEJ contributes to cell survival following cisplatin treatment. In clinical settings, higher <em>PRKDC</em> expression correlates with poorer survival, while elevated <em>RAD54L</em> and <em>POLQ</em> expression correlates with better survival in cisplatin-treated cervical and head and neck cancers. These findings reflect the opposing roles of NHEJ versus HR and TMEJ in replication-associated DSB repair, as observed <em>in vitro</em>.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103889"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004361","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

Innate immune sensing and signaling: Co-opted for genome surveillance? Implications for tumorigenesis 先天免疫感知和信号传导：基因组监测的增选？对肿瘤发生的影响

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-09-01 Epub Date: 2025-09-07 DOI: 10.1016/j.dnarep.2025.103890

Hexiao Wang, John H.J. Petrini

{"title":"Innate immune sensing and signaling: Co-opted for genome surveillance? Implications for tumorigenesis","authors":"Hexiao Wang, John H.J. Petrini","doi":"10.1016/j.dnarep.2025.103890","DOIUrl":"10.1016/j.dnarep.2025.103890","url":null,"abstract":"<div><div>Innate immune signaling is traditionally associated with the response to pathogenic infection. However, emerging evidence suggests that nuclear innate immune sensors and their downstream pathways may also serve as a critical mechanism for genome surveillance. This review explores a model in which DNA sensors such as mouse IFI204 and IFI205 (IFI16 in humans) localize to replication forks, where they detect endogenous aberrant DNA structures and initiate an interferon-stimulated gene (ISG) transcriptional program. A key output of this transcriptional program is ISG15, which we find conjugated to fork-associated proteins and facilitates recruitment of the replication fork protection complex, thereby stabilizing replication forks under physiological conditions. We discuss how nuclear innate immune sensors mediate replication stress sensing and examine the broad consequences of downstream ISG transcription across diverse contexts—including its impact on genome stability and its dual roles in modulating tumor cell behavior and the tumor microenvironment. These findings suggest that the innate immune system, through its nuclear DNA sensing arm, may be evolutionarily co-opted for genome surveillance and may influence tumor initiation and therapy resistance. Understanding how innate immune signaling intersects with replication stress could offer mechanistic insights into tumor development and reveal novel therapeutic targets.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103890"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026420","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

S-palmitoylation: An oily modification guardinggenome stability s -棕榈酰化：一种保护基因组稳定性的油性修饰

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-09-01 Epub Date: 2025-08-08 DOI: 10.1016/j.dnarep.2025.103883

Xiyuan Zheng , Xinying Wu , Lei Wang , Haohong Ouyang , Yeltokova Damira , Bin Peng , Xingzhi Xu

引用次数: 0

DNA repair at the crossroads of tumor immunogenicity and cancer therapy: Harnessing innate and adaptive immune pathways for improved therapeutic outcomes DNA修复在肿瘤免疫原性和癌症治疗的十字路口：利用先天和适应性免疫途径改善治疗效果

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-08-01 Epub Date: 2025-07-22 DOI: 10.1016/j.dnarep.2025.103874

Zhanfeng Liang , Yangrui Xu , Chuan-Yuan Li

{"title":"DNA repair at the crossroads of tumor immunogenicity and cancer therapy: Harnessing innate and adaptive immune pathways for improved therapeutic outcomes","authors":"Zhanfeng Liang , Yangrui Xu , Chuan-Yuan Li","doi":"10.1016/j.dnarep.2025.103874","DOIUrl":"10.1016/j.dnarep.2025.103874","url":null,"abstract":"<div><div>Immunotherapy has revolutionized cancer treatment, particularly with immune checkpoint inhibitors (ICIs), which harness the immune system to achieve durable antitumor responses. DNA repair pathways, essential for maintaining genomic stability, play a complex role in cancer. While functional DNA repair prevents tumorigenesis, deficiencies in pathways such as homologous recombination (HR), mismatch repair (MMR), and non-homologous end joining (NHEJ) can amplify tumor immunogenicity. These deficiencies increase tumor mutational burden, generate neoantigens, and activate innate immune sensors like cGAS–STING and RIG-I/MDA5-MAVS. Therapies such as radiotherapy and chemotherapy can enhance these effects by inducing DNA damage and de-repressing endogenous retroviral elements, creating a \"viral mimicry\" state that promotes immune recognition. Thus, combining DNA repair inhibitors with cytotoxic therapies and immunotherapy has emerged as a promising strategy to enhance antitumor immunity. This review highlights mechanisms by which DNA repair defects and genotoxic stress activate innate immunity, improve antigen presentation, and foster T-cell activation. Emerging approaches integrating PARP and ATM/ATR inhibitors with ICIs, STING agonists, and cancer vaccines offer potential to overcome immune resistance. Personalized combinations tailored to tumor-specific DNA repair and immune profiles hold promises for transforming cancer treatment, with ongoing research aimed at optimizing therapeutic efficacy while minimizing toxicity.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103874"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723962","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

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 : 2025-08-01 Epub Date: 2025-06-24 DOI: 10.1016/j.dnarep.2025.103863

Joséphine Groslambert , Kira Schützenhofer , Luca Palazzo , Ivan Ahel

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 : 2025-08-01 Epub 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":"2025-08-01","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

DNA damage repair (DDR) related prognostic risk model in multiple myeloma based on single-cell and bulk sequencing 基于单细胞和批量测序的多发性骨髓瘤DNA损伤修复（DDR）相关预后风险模型

IF 3 3区生物学

DNA Repair Pub Date : 2025-08-01 Epub Date: 2025-06-13 DOI: 10.1016/j.dnarep.2025.103857

Hongxiu Liu , Zhihua Li , Yihua Wang , Can Li , Kaiqing Yan , Yanping Ma

{"title":"DNA damage repair (DDR) related prognostic risk model in multiple myeloma based on single-cell and bulk sequencing","authors":"Hongxiu Liu , Zhihua Li , Yihua Wang , Can Li , Kaiqing Yan , Yanping Ma","doi":"10.1016/j.dnarep.2025.103857","DOIUrl":"10.1016/j.dnarep.2025.103857","url":null,"abstract":"<div><div>Genomic rearrangements and instability are key pathological features of multiple myeloma (MM). However, the origins of DNA damage in MM and its impact on disease progression remain incompletely understood. Here, we screened DNA damage repair (DDR) genes from single-cell RNA sequencing and bulkRNA-seq datasets using WGCNA and differential expression analysis. A prognostic model was constructed, demonstrating that patients in high DDR expression group had poor outcomes in both the training and validation cohorts. The nomogram also indicated that DDR-related risk scores had good predictive performance. Then, the differences of immune infiltration and mutation landscape between low and high DDR group were investigated. PARP1, PCNA, and RAD23A were identified as key DDR-related genes in MM. Additionally, we explored the drug sensitivity and potential molecular mechanisms associated with each key gene. Altogether, the DDR-related prognostic risk model in MM may facilitate risk stratification and guide treatment decisions, with key prognostic genes might potentially serving as biomarkers and therapeutic targets.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103857"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307976","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 : 2025-08-01 Epub 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":"2025-08-01","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

Harnessing R-loop dynamics: Challenging cancer therapy resistance 利用r环动力学：挑战癌症治疗耐药性

IF 3 3区生物学

DNA Repair Pub Date : 2025-08-01 Epub Date: 2025-06-11 DOI: 10.1016/j.dnarep.2025.103859

Michele Giaquinto, Alessandro Framarini, Andrea Parlante, Stefan Schoeftner

{"title":"Harnessing R-loop dynamics: Challenging cancer therapy resistance","authors":"Michele Giaquinto, Alessandro Framarini, Andrea Parlante, Stefan Schoeftner","doi":"10.1016/j.dnarep.2025.103859","DOIUrl":"10.1016/j.dnarep.2025.103859","url":null,"abstract":"<div><div>R-loops are atypical three-stranded nucleic acid structures composed of a stretch of DNA:RNA hybrids that displace the unpaired, single DNA strand, resulting in the formation of a characteristic loop structure. When properly regulated, R-loops have been demonstrated to control crucial processes related to RNA metabolism, epigenetic gene regulation, DNA damage repair, homologous recombination, and DNA replication. However, unscheduled R-loops can induce DNA damage, thus compromising genome stability. In line with these central features, cancer cells frequently exhibit deregulated R-loop metabolism. The action of oncogenes or mutant tumor suppressor genes is associated with alterations in R-loop levels, which in turn can disrupt physiological processes or drive cancer genome instability. A panel of antineoplastic drugs that interfere with R-loop prevention, resolution or processing has been shown to exacerbate R-loop-mediated genome instability, modulate immunity pathways and mediate cell death. Mechanisms of resistance to these drugs are expected to include the activation of pathways that counteract R-loop-mediated genome instability. In this review, we will discuss key regulators of R-loops in cancer cells, therapeutic strategies that promote R-loop formation and the relevance of R-loops for cancer therapy resistance.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103859"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322419","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