DNA Repair最新文献_第2页

Proofreading exonuclease activities of Polδ and Polε differentially contribute to the removal of chain-terminating nucleoside analogs 校对Polδ和Polε的核酸外切酶活性对链终止核苷类似物的去除有不同的作用

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-08-14 DOI: 10.1016/j.dnarep.2025.103885

Eri Nishizawa , Hiromori Ohkubo , Ryotaro Kawasumi , Masataka Tsuda , Kouji Hirota

{"title":"Proofreading exonuclease activities of Polδ and Polε differentially contribute to the removal of chain-terminating nucleoside analogs","authors":"Eri Nishizawa , Hiromori Ohkubo , Ryotaro Kawasumi , Masataka Tsuda , Kouji Hirota","doi":"10.1016/j.dnarep.2025.103885","DOIUrl":"10.1016/j.dnarep.2025.103885","url":null,"abstract":"<div><div>Chain-terminating nucleoside analogs (CTNAs) are incorporated into genome during replication by replicative polymerase delta (Polδ) and epsilon (Polε), then inhibit DNA synthesis by preventing subsequent polymerization. The proofreading exonuclease activity of Polε removes the incorporated CTNAs, thereby contributing to cellular tolerance to these drugs. However, the contribution of Polδ’s proofreading exonuclease activity has not been clarified, nor has the relationship between Polδ and Polε been well understood. We here show that Polδ’s exonuclease activity contributes to the cellular tolerance to CTNAs, with the role of Polδ and Polε exonucleases differing depending on the kinds of CTNAs. We tested the sensitivity of <em>POLD1</em><sup><em>exo−/+</em></sup> cells to a CTNA, Ara-C, and found that expression of the exonuclease deficient Polδ sensitizes cells to Ara-C. Furthermore, the exonuclease deficient Polδ reduced cell viability upon Ara-C to the same extent in both Polε exonuclease-proficient and -deficient cells, indicating that these two polymerases independently contribute to cellular tolerance to Ara-C. In contrast, wild-type, <em>POLD1</em><sup><em>exo−/+</em></sup>, and <em>POLE1</em><sup><em>exo−/−</em></sup> cells exhibited similar sensitivity to ddC, AZT, and alovudine, whilst <em>POLD1</em><sup><em>exo−/+</em></sup>/<em>POLE1</em><sup><em>exo−/−</em></sup> cells were considerably more sensitive compared with these cells, indicating that Polδ and Polε compensate for each other. Finally, we found that exonuclease activities of replicative polymerases cannot remove ACV from the end of nascent DNA. Taken together, our findings show that CTNAs have a differential impact on the replication fork, and the requirement of the exonuclease activities of replicative polymerases varies depending on the kinds of CTNAs.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"153 ","pages":"Article 103885"},"PeriodicalIF":2.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144864214","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 : 2025-08-08 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

The model moss Physcomitrium patens relies heavily on homologous recombination to repair DNA double-strand breaks 模式苔藓壶状菌主要依靠同源重组修复DNA双链断裂

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-08-01 DOI: 10.1016/j.dnarep.2025.103881

Ayako N. Sakamoto , Yuichiro Yokota , Pierre-François Perroud , Yasuhiro Oshima , Fabien Nogué , Yoshihiro Hase

{"title":"The model moss Physcomitrium patens relies heavily on homologous recombination to repair DNA double-strand breaks","authors":"Ayako N. Sakamoto , Yuichiro Yokota , Pierre-François Perroud , Yasuhiro Oshima , Fabien Nogué , Yoshihiro Hase","doi":"10.1016/j.dnarep.2025.103881","DOIUrl":"10.1016/j.dnarep.2025.103881","url":null,"abstract":"<div><div>We previously showed that moss (<em>Physcomitrium patens</em>) cells are highly radioresistant and suggested that <em>P. patens</em> uses an efficient mechanism to repair DNA double-strand breaks (DSBs). Homologous recombination (HR), canonical non-homologous end-joining, and alternative end-joining are the major pathways used to repair DSBs. To identify the DSB repair pathway used in <em>P. patens</em>, we generated knockout (KO) plants for <em>LIG4</em>, <em>POLQ</em>, and <em>RAD51B</em>, which play major roles in canonical non-homologous end-joining, alternative end-joining, and HR, respectively. The KO plants were irradiated with γ-rays, and their radioresistance was evaluated. Although wild-type (WT), <em>lig4</em>, and <em>polq</em> plants showed comparable radioresistance, that of <em>rad51b</em> plants was drastically reduced. The radioresistance of <em>rad51b polq</em> plants was further reduced, whereas that of <em>rad51b lig4</em> plants was similar to that of <em>rad51b</em>. Under γ-irradiation conditions at which the dry weight of the plants was reduced to 50 %, single base substitutions were predominantly induced in WT, <em>lig4</em>, and <em>polq</em> plants. In contrast, drastic sequence alterations, such as large deletions with or without insertions, chromosome inversions, or translocations, were induced in <em>rad51b</em> and <em>rad51b polq</em> plants. These results suggest that <em>P. patens</em> primarily uses the HR pathway for DSB repair, even in the presence of other pathways. Flow cytometry analysis of the WT and KO plants revealed that the majority of cells subjected to irradiation were in late S/G2 phase, suggesting that the sister chromatid served as a template for HR.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103881"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826917","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

The role of DNA repair deficiency in lipid accumulation: A proof-of-concept study DNA修复缺陷在脂质积累中的作用：一项概念验证研究

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-08-01 DOI: 10.1016/j.dnarep.2025.103880

Houan Tu , Ibbo Willems , Anastasiya Mircheva , Victoria Claudino Bastos , Twan van den Beucken , Ludwig Dubois , Alexander H.V. Remels , Frederik-Jan van Schooten , Roger W.L. Godschalk , Sabine A.S. Langie

{"title":"The role of DNA repair deficiency in lipid accumulation: A proof-of-concept study","authors":"Houan Tu , Ibbo Willems , Anastasiya Mircheva , Victoria Claudino Bastos , Twan van den Beucken , Ludwig Dubois , Alexander H.V. Remels , Frederik-Jan van Schooten , Roger W.L. Godschalk , Sabine A.S. Langie","doi":"10.1016/j.dnarep.2025.103880","DOIUrl":"10.1016/j.dnarep.2025.103880","url":null,"abstract":"<div><div>Animal models suggest an association between base excision repair (BER) deficiency and increased risk of obesity. To mechanistically investigate the effect of BER deficiency on intracellular lipid accumulation, we studied metabolic activity in <em>in vitro</em> BER knockdown (KD) models, targeting <em>MutY DNA Glycosylase (MUTYH), Nth Like DNA Glycosylase 1 (NTHL1) and 8-Oxoguanine DNA Glycosylase (OGG1)</em>. We hypothesized that exposing BER deficient cells to lipids leads to reduced mitochondrial function and enhanced intracellular lipid accumulation. Stable BER KD models were generated in HepG2 cells using lentiviral shRNAs. KD was confirmed by qRT-PCR and BER activity was assessed using a modified comet assay. Upon exposure to a mixture of oleic and palmitic acid, DNA damage and mitochondrial copy number were only altered in <em>NTHL1</em>-KD cells, but all KD cells accumulated more intracellular lipids compared to <em>lacZ</em> control cells as determined by Oil-Red-O (ORO) staining. Compared to control cells, exposure to the fatty acid mixture increased proton leak in <em>MUTYH</em>-KD cells, indicating impaired mitochondrial function. Moreover, all KD cells showed reduced β-oxidation activity when exposed to the fatty acid mixture. Overall, this study shows that BER deficient HepG2 cells are more prone to accumulated lipids, which was associated with impaired mitochondrial function. These findings are relevant in understanding the underlying mechanisms that modulate the sensitivity of a person to accumulate lipids and increase their risk of developing metabolic diseases such as obesity and fatty liver disease.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103880"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780927","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

Cytosolic DNA and intracellular Ca2+: Maintaining genome stability during replication stress 胞质DNA和细胞内Ca2+：在复制胁迫下维持基因组的稳定性

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-08-01 DOI: 10.1016/j.dnarep.2025.103877

Shan Li , Hsiang-Ting Lu , Zhongsheng You

{"title":"Cytosolic DNA and intracellular Ca2+: Maintaining genome stability during replication stress","authors":"Shan Li , Hsiang-Ting Lu , Zhongsheng You","doi":"10.1016/j.dnarep.2025.103877","DOIUrl":"10.1016/j.dnarep.2025.103877","url":null,"abstract":"<div><div>Maintaining genome stability during DNA replication is a critical cellular challenge. Various surveillance and repair mechanisms have evolved to cope with replication stress, which can be caused by environmental insults, metabolic byproducts, complex DNA structures in the genome, and replication-transcription conflicts. This perspective highlights a newly identified cytosolic DNA/Ca<sup>2+</sup>-dependent signaling pathway that plays a crucial role in protecting stalled replication forks. The pathway involves cytosolic DNA generation and its sensing by the cGAS-cGAMP-STING axis, TRPV2-mediated Ca<sup>2+</sup> release from the ER, and activation of a CaMKK2-AMPK protein phosphorylation cascade that suppresses the EXO1 nuclease, thereby preventing aberrant fork processing and preserving chromosomal integrity. Separate from the ATR/Chk1 checkpoint, this cytoDNA/Ca<sup>2+</sup>-dependent pathway represents a non-redundant mechanism for genome maintenance, with potentially important implications for cancer formation and its treatment. Moreover, the intersection of this pathway with other signaling networks also enables coordinated regulation of genome maintenance, immune response, autophagy, and cellular senescence.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103877"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763874","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 response of U2OS cells to low doses of gamma radiation delivered at very low dose rate U2OS细胞对低剂量极低剂量率γ辐射的DNA损伤反应

IF 2.7 3区生物学

DNA Repair Pub Date : 2025-07-23 DOI: 10.1016/j.dnarep.2025.103875

Magdalena Płódowska , Wiktoria Krakowiak , Aneta Węgierek-Ciuk , Katarzyna Gałczyńska , Kinga Pasińska , Daniel Sobota , Paweł Wołowiec , Janusz Braziewicz , Anna Lankoff , Michał Arabski , Andrzej Wojcik , Halina Lisowska

{"title":"DNA damage response of U2OS cells to low doses of gamma radiation delivered at very low dose rate","authors":"Magdalena Płódowska , Wiktoria Krakowiak , Aneta Węgierek-Ciuk , Katarzyna Gałczyńska , Kinga Pasińska , Daniel Sobota , Paweł Wołowiec , Janusz Braziewicz , Anna Lankoff , Michał Arabski , Andrzej Wojcik , Halina Lisowska","doi":"10.1016/j.dnarep.2025.103875","DOIUrl":"10.1016/j.dnarep.2025.103875","url":null,"abstract":"<div><div>The DNA damage response (DDR) of cells to low dose and low dose rate ionizing radiation is weak and remains a matter of controversy. The response can be studied by exposing cells to a low adapting dose (AD) and, subsequently to a high challenging dose (CD), where the response is strong. The aim of the present investigation was to analyse the DDR in cells exposed to very low dose rate AD and a high dose rate CD, with special focus on the role of the ATM kinase. U2OS cells (with wild type p53) were exposed to gamma radiation AD of 5.9 mGy at 31 µGy/h and of 10.5 mGy at 55 µGy/h. ATM was inhibited by addition of KU-55933. Adapted cells were exposed to a CD of 1 Gy photon radiation at 1 Gy/min. The studied endpoints included kinetics of 53BP1 foci formation and decay, cell cycle progression and gene expression. In some experiments, ATM was inhibited by KU-55933. AD alone led to a significant increase in 53BP1 foci, even in the presence of KU-55933, and it modulated the response to CD. KU-55933 failed to inhibit the induction of foci by AD and AD+CD, while foci induction by CD alone was inhibited. KU-55933 potentiated the G2 block in AD+CD-exposed cells. Gene expression was modulated by AD. In conclusion, AD differentially modulated the response of cells when given alone and after the CD, in absence and presence of KU-55933.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"152 ","pages":"Article 103875"},"PeriodicalIF":2.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722060","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

Using the safety scissors: DNA resection regulation at DNA double-strand breaks and telomeres 使用安全剪刀：DNA双链断裂和端粒的DNA切除调控

IF 3 3区生物学

DNA Repair Pub Date : 2025-07-23 DOI: 10.1016/j.dnarep.2025.103876

Michael M. Soniat , Logan R. Myler

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 : 2025-07-22 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":"2025-07-22","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

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