DNA Repair最新文献_第4页

DNA damage response and genomic instability disorder: Meeting report of the 20th Ataxia-Telangiectasia Workshop (ATW-2024) in conjunction with the 15th international symposium on DNA damage response & human disease (isDDRHD-2024) DNA损伤反应与基因组不稳定性疾病：第20届共济失调-毛细血管扩张研讨会（ATW-2024）与第15届DNA损伤反应与人类疾病国际研讨会（isDDRHD-2024）会议报告

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-17 DOI: 10.1016/j.dnarep.2025.103860

Yisui Xia , Zhao-Qi Wang , Xingzhi Xu

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 : 2025-06-13 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":"2025-06-13","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

Treatment of human cells with the anti-cancer drug cisplatin results in the caspase-dependent release of adduct-containing cell-free DNA 用抗癌药物顺铂治疗人类细胞导致caspase依赖性释放含加合物的无细胞DNA

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-12 DOI: 10.1016/j.dnarep.2025.103855

Sri Meghana Yerrapragada , Aleena Alex , Sheera Adar , Michael G. Kemp , M. Alexandra Carpenter

{"title":"Treatment of human cells with the anti-cancer drug cisplatin results in the caspase-dependent release of adduct-containing cell-free DNA","authors":"Sri Meghana Yerrapragada , Aleena Alex , Sheera Adar , Michael G. Kemp , M. Alexandra Carpenter","doi":"10.1016/j.dnarep.2025.103855","DOIUrl":"10.1016/j.dnarep.2025.103855","url":null,"abstract":"<div><div>Cell-free DNA (cfDNA) found in biofluids is increasingly being used in the diagnosis and treatment of a variety of disease states, including cancer. Though DNA is known to be susceptible to damage by many different chemotherapeutic compounds and genotoxic agents, the fact that cfDNA may be damaged and contain DNA adducts associated with specific exposures has not previously been considered to any significant extent. Here, using differential centrifugation of culture medium from cells treated with the anti-cancer drug cisplatin, we show that DNA containing cisplatin adducts is readily detectable in the extracellular milieu and is enriched in fractions known to contain small extracellular vesicles and cfDNA. However, our data indicates that this damaged cfDNA is non-vesicular in nature and likely represents fragments of chromatin. Dose and time course experiments suggest that the release of cfDNA containing cisplatin-DNA adducts is correlated with the activation of apoptotic signaling. Indeed, the generation of cisplatin-damaged cfDNA is exacerbated by the loss of nucleotide excision repair and is abrogated by caspase inhibition. Finally, we show that native cisplatin-damaged cfDNA, but not purified, protein-free cfDNA, can be taken up by cells by phagocytosis to result in the presence of cisplatin-DNA adduct-containing DNA in non-cisplatin-treated cells. These results indicate that tumors from patients undergoing cisplatin-based chemotherapy may shed damaged cfDNA that could have additional biological effects in bystander cells, which could both impact chemotherapeutic responses and lead to improved treatments and diagnostic tools for monitoring therapeutic efficacy.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"151 ","pages":"Article 103855"},"PeriodicalIF":3.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263756","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 : 2025-06-11 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":"2025-06-11","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

"Yin-Yang" of PARP1 in genotoxic and inflammatory response PARP1基因毒性和炎症反应的“阴阳”关系

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-11 DOI: 10.1016/j.dnarep.2025.103858

Sijia Wang , Yukang Wu , Wen Zong , Zhao-Qi Wang

引用次数: 0

Checkpoint activation and recovery: regulation of the 9–1–1 axis by the PP2A phosphatase 检查点激活和恢复：PP2A磷酸酶对9-1-1轴的调控

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-06 DOI: 10.1016/j.dnarep.2025.103854

Erika Casari, Renata Tisi, Maria Pia Longhese

{"title":"Checkpoint activation and recovery: regulation of the 9–1–1 axis by the PP2A phosphatase","authors":"Erika Casari, Renata Tisi, Maria Pia Longhese","doi":"10.1016/j.dnarep.2025.103854","DOIUrl":"10.1016/j.dnarep.2025.103854","url":null,"abstract":"<div><div>Genome integrity is continuously monitored by elaborate cellular networks, collectively referred to as the DNA damage response (DDR), which detect DNA lesions and transmit the information to downstream targets, thereby coordinating a broad range of biological processes. A crucial signal in this response is the generation of single-stranded DNA that, once coated by replication protein A (RPA), serves as a platform for recruiting the apical checkpoint kinase Mec1/ATR. Full activation of Mec1/ATR also requires the 9–1–1 complex, which provides a docking site for additional checkpoint mediators, such as Dpb11/TOPBP1 and Rad9/53BP1. These mediators are important for transducing the checkpoint signal from Mec1/ATR to the effector kinase Rad53/CHK2. The checkpoint signal transduction cascade is tightly regulated by phosphorylation events, which can be counteracted by phosphatases to ensure timely checkpoint inactivation once DNA repair is complete. In this review, we examine the mechanistic aspects of Mec1/ATR activation, with a particular focus on the 9–1–1 checkpoint axis in <em>Saccharomyces cerevisiae</em>. We discuss how phosphorylation and dephosphorylation dynamically regulate the checkpoint pathway, allowing cells to efficiently respond to genotoxic stress while ensuring a timely return to normal cell-cycle progression.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"151 ","pages":"Article 103854"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241103","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

Initiation of base excision repair is modulated by nucleosome occupancy modifying sequences 碱基切除修复的启动是由核小体占用修饰序列调节的

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-01 DOI: 10.1016/j.dnarep.2025.103852

Giovannia M. Barbosa, Sarah Delaney

{"title":"Initiation of base excision repair is modulated by nucleosome occupancy modifying sequences","authors":"Giovannia M. Barbosa, Sarah Delaney","doi":"10.1016/j.dnarep.2025.103852","DOIUrl":"10.1016/j.dnarep.2025.103852","url":null,"abstract":"<div><div>Nucleosome occupancy varies across the genome and plays a critical role in modulating DNA accessibility. While the effect of occupancy on gene expression has been studied, its influence on DNA repair, particularly base excision repair (BER), remains unexplored. In this work, we investigate the relationship between nucleosome occupancy and the initiation of BER by reconstituting nucleosome core particles (NCPs) using four DNA sequences known to modulate nucleosome occupancy <em>in vivo</em>. The results demonstrate that histone-DNA interactions differ significantly among these sequences. Moreover, uracil DNA glycosylase (UDG) activity is limited to solution-accessible uracil (U) lesion sites on NCPs containing the high occupancy sequences M4 and SB. In contrast, UDG displays high activity on NCPs containing the low occupancy sequences M2 and M3, even at less solution accessible lesion sites. In fact, for NCPs containing the sequence with the lowest occupancy, M2, UDG exhibits high activity regardless of the U lesion position. However, this high level of activity regardless of lesion position was not observed for thymine DNA glycosylase (TDG) and single-stranded monofunctional uracil DNA glycosylase 1 (SMUG1). Instead, the activity of TDG was dictated by the sequence flanking the U with a preference for 5′-UpG-3′ and 5′-UpA-3′ sequences, consistent with the role of TDG in epigenetic regulation. SMUG1 activity is high at many U sites but is severely hindered in the dyad region. These results highlight the interplay between nucleosome occupancy and BER, offering new insights into the dynamics of chromatin and DNA repair.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"150 ","pages":"Article 103852"},"PeriodicalIF":3.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177901","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 polymerase beta expression in head & neck cancer modulates the poly(ADP-ribose)-mediated replication checkpoint DNA聚合酶β在头颈癌中的表达调节poly（adp -核糖）介导的复制检查点

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-01 DOI: 10.1016/j.dnarep.2025.103853

Md Maruf Khan , Wynand P. Roos , Charlotte R. Pearson , Stefan M. Leonard , Anusha Angajala , Denise Y. Gibbs , Jeffrey C. Liu , Camille Ragin , Robert W. Sobol

{"title":"DNA polymerase beta expression in head & neck cancer modulates the poly(ADP-ribose)-mediated replication checkpoint","authors":"Md Maruf Khan , Wynand P. Roos , Charlotte R. Pearson , Stefan M. Leonard , Anusha Angajala , Denise Y. Gibbs , Jeffrey C. Liu , Camille Ragin , Robert W. Sobol","doi":"10.1016/j.dnarep.2025.103853","DOIUrl":"10.1016/j.dnarep.2025.103853","url":null,"abstract":"<div><div>Head and Neck Squamous Cell Carcinoma (HNSCC) imposes a significant health burden, necessitating innovative therapeutic strategies to enhance treatment efficacy. Current treatments, such as surgery, radiation, and chemotherapy, have limited effectiveness and yield severe side effects, emphasizing the need for targeted therapies. We have focused on DNA polymerase beta (Polβ) and its roles in replication stress, cellular responses to DNA damaging-therapies, and DNA damage response modifiers. Our investigations reveal a regulatory role for base excision repair (BER) proteins, including Polβ, in the cellular response to inhibitors of poly(ADP-ribose) glycohydrolase (PARG), an enzyme involved in poly(ADP-ribose) (PAR) degradation. The inhibition of PARG, in HNSCC cells, elicits replication stress and activates the PAR-induced S-phase/ATR checkpoint, leading to a block to replication, cell cycle arrest, and the onset of apoptosis. However, Polβ overexpression mitigates this response, reducing replication-stress-induced PAR foci formation, suggesting a modulation of replication checkpoint activation. We found that PARG inhibitor treatment is ineffective on HNSCC cells that overexpress Polβ, implying that the PARG inhibitor-induced PAR and apoptotic response is dependent on the level of Polβ. Further, our in vitro experiments demonstrate that combining PARG and ATR/CHK1 inhibitors overcomes Polβ-mediated treatment resistance in HNSCC cells, producing synergistic effects compared to the individual treatment conditions. Our findings suggest a possible treatment paradigm for HNSCC, employing ATR or CHK1 inhibitors in combination with PARG inhibitors. This strategy offers a promising path for more effective HNSCC treatments, potentially overcoming Polβ-related resistance.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"150 ","pages":"Article 103853"},"PeriodicalIF":3.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205275","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

Dynamics of chromatin factors RSF1, CENPS and CENPX at DNA damage sites 染色质因子RSF1、CENPS和CENPX在DNA损伤位点的动态变化

IF 3 3区生物学

DNA Repair Pub Date : 2025-06-01 DOI: 10.1016/j.dnarep.2025.103850

Pritishkumar Tidke , Andrew Flaus , Helen Dodson

{"title":"Dynamics of chromatin factors RSF1, CENPS and CENPX at DNA damage sites","authors":"Pritishkumar Tidke , Andrew Flaus , Helen Dodson","doi":"10.1016/j.dnarep.2025.103850","DOIUrl":"10.1016/j.dnarep.2025.103850","url":null,"abstract":"<div><div>Chromatin has a major influence on the DNA damage response (DDR). Several chromatin-related factors participate in specialised DNA packaging during the DDR including the CENPS and CENPX histone fold proteins, also known as MHF1/2, and the chromatin remodelling factor RSF1 although their contribution has remained unclear. We defined a timeline for RSF1, CENPS, and CENPX recruitment at DNA double strand breaks (DSBs) induced in live HeLa cells by microirradiation and calibrated this to published data to clarify the potential for their involvement in the DDR. CENPS, CENPX and RSF1 are recruited with a half time of ∼100 s and removed with a half time of ∼2000 s. Enrichment for cell cycle phase revealed that this recruitment occurs in G1, S and G2 phases, but that its half time in G2 appears to be delayed and stronger than in G1. Integration of these observations with timelines for other DDR factors reveals that CENPS and CENPX recruitment occurs simultaneously immediately after ATM activation and RNF8-RNF168 activity. The removal of CENPS and CENPX is at a similar time to loading of RPA and assembly of RAD51. This places RSF1, CENPS and CENPX in the vicinity of DSBs at the time when nucleosomes are being actively remodelled during the chromatin-dependent early response to DNA damage involving pathway choice and resection, and their increased abundance at DSBs in G2 correlates with extended resection for HR.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"150 ","pages":"Article 103850"},"PeriodicalIF":3.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189396","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

Development and characterization of a novel NEIL1 nanobody 一种新型NEIL1纳米体的研制与表征

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-22 DOI: 10.1016/j.dnarep.2025.103849

Marlo K. Thompson , Mark H. Eggers , Danielle Flores , Israel Valenzuela , Zhengrong Yang , Joel F. Andrews , Tom Johnsten , Aishwarya Prakash

{"title":"Development and characterization of a novel NEIL1 nanobody","authors":"Marlo K. Thompson , Mark H. Eggers , Danielle Flores , Israel Valenzuela , Zhengrong Yang , Joel F. Andrews , Tom Johnsten , Aishwarya Prakash","doi":"10.1016/j.dnarep.2025.103849","DOIUrl":"10.1016/j.dnarep.2025.103849","url":null,"abstract":"<div><div>Nei endonuclease VIII-like 1 (NEIL1) is a bifunctional human DNA glycosylase that catalyzes the first step of the base excision repair (BER) pathway by recognizing and excising oxidized bases, including thymine glycol and the further oxidation products of 7,8-dihydro-8-oxoguanine (8-oxoG), spiroiminodihydantoin, and guanidinohydantoin. Despite its critical role in maintaining genome stability, NEIL1 is expressed at relatively low endogenous cellular levels compared to other BER proteins such as OGG1, Polβ, and APE1. As a result, most cellular studies have relied on overexpression systems. Additionally, progress in studying NEIL1 has been hindered by the inconsistent availability and continuity of specific commercially available antibodies. To address this challenge, we developed single-domain nanobodies (VHHs) targeting NEIL1. A yeast 2 hybrid (Y2H) screen identified ten VHH hits with the top candidate, henceforth called A5, emerging multiple times. Here, we characterize the binding properties of A5 using a combination of biochemical and molecular techniques. Differential scanning fluorimetry and glycosylase activity assays indicate that recombinant A5 specifically stabilizes recombinantly expressed NEIL1, while not interfering with its glycosylase activity. Moreover, our data suggest that A5 preferentially binds to NEIL1’s N-terminal glycosylase domain rather than its C-terminal flexible tail, which is known to mediate protein-protein interactions. In live-cell imaging studies, an A5-mCherry chromobody colocalizes with NEIL1-GFP and is recruited to sites of laser-induced DNA damage, suggesting its potential as a molecular tool for visualizing NEIL1 dynamics. These findings establish A5 as a valuable probe for studying NEIL1 function and opens new avenues for exploring its role in DNA repair.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"150 ","pages":"Article 103849"},"PeriodicalIF":3.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169572","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