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Overexpression of the WWE domain of RNF146 modulates poly-(ADP)-ribose dynamics at sites of DNA damage RNF146的WWE结构域的过表达可调节DNA损伤位点的多核苷酸动力学

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-21 DOI: 10.1016/j.dnarep.2025.103845

Rasha Q. Al-Rahahleh , Wynand P. Roos , Kate M. Saville , Joel F. Andrews , Zhijin Wu , Christopher A. Koczor , Aishwarya Prakash , Robert W. Sobol

{"title":"Overexpression of the WWE domain of RNF146 modulates poly-(ADP)-ribose dynamics at sites of DNA damage","authors":"Rasha Q. Al-Rahahleh , Wynand P. Roos , Kate M. Saville , Joel F. Andrews , Zhijin Wu , Christopher A. Koczor , Aishwarya Prakash , Robert W. Sobol","doi":"10.1016/j.dnarep.2025.103845","DOIUrl":"10.1016/j.dnarep.2025.103845","url":null,"abstract":"<div><div>Protein poly-ADP-ribosylation (PARylation) is a post-translational modification formed by transferring successive units of ADP-ribose to target proteins to form poly-ADP-ribose (PAR) chains. PAR plays a critical role in the DNA damage response (DDR) by acting as a signaling platform to promote the recruitment of DNA repair factors to the sites of DNA damage that bind via their PAR-binding domains (PBDs). Several classes of PBD families have been identified, which recognize distinct parts of the PAR chain. Proteins encoding PBDs play an essential role in conveying the PAR-mediated signal through their interaction with PAR chains, which mediates many cellular functions, including the DDR. The WWE domain, encoded in 12 human proteins, identifies the iso-ADP-ribose moiety of the PAR chain. PARylation is a heterogeneous structure that is highly dynamic in cells. Capturing the dynamics of PARylation is essential to understanding its role in the DDR, which can be achieved by expanding the tool kit for PAR detection and tracking mediated by the unique binding capability of various sensors. We recently described the WWE domain of RNF146 as a robust genetically encoded probe, when fused to EGFP, for the detection of PAR in live cells. Expanding on this, we used structural prediction tools to evaluate all of the WWE domains encoded in human proteins, evaluating each as molecular PAR probes in live cells. We demonstrate unique PAR dynamics when tracked by WWE-encoded PAR binding domains, in addition to an engineered macrodomain, that can be exploited for modulation of the PAR-dependent DNA damage response.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"150 ","pages":"Article 103845"},"PeriodicalIF":3.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144106402","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

PARP1-PROTACs providing novel opportunities in precision oncology by targeting DNA damage response PARP1-PROTACs通过靶向DNA损伤反应为精确肿瘤学提供了新的机会

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-21 DOI: 10.1016/j.dnarep.2025.103851

Md Sadique Hussain, Gaurav Gupta

引用次数: 0

BRCA1 and BRCA2 in DNA damage and replication stress response: Insights into their functions, mechanisms, and implications for cancer treatment BRCA1和BRCA2在DNA损伤和复制应激反应中的作用、机制及其对癌症治疗的影响

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-13 DOI: 10.1016/j.dnarep.2025.103847

Ziqi Xu , Haihua Xie , Lizhi Song , Yuhua Huang , Jun Huang

{"title":"BRCA1 and BRCA2 in DNA damage and replication stress response: Insights into their functions, mechanisms, and implications for cancer treatment","authors":"Ziqi Xu , Haihua Xie , Lizhi Song , Yuhua Huang , Jun Huang","doi":"10.1016/j.dnarep.2025.103847","DOIUrl":"10.1016/j.dnarep.2025.103847","url":null,"abstract":"<div><div>Genomic stability is a cornerstone of cellular survival and proliferation. To counter the constant threat posed by endogenous and exogenous DNA-damaging agents, cells rely on a network of intricate mechanisms to safeguard DNA integrity and ensure accurate replication. Among these, the BRCA1 and BRCA2 tumor suppressor proteins play pivotal roles. While traditionally recognized for their involvement in homologous recombination repair and cell cycle checkpoints, emerging evidence highlights their essential functions in protecting stalled replication forks during replication stress. Mutations in BRCA1 or BRCA2 disrupt these critical functions, leading to compromised genome stability and an increased susceptibility to various cancers, particularly breast and ovarian cancers. This review provides a comprehensive analysis of the multifaceted roles of BRCA1 and BRCA2, focusing on their contributions to DNA damage responses and replication stress management. By elucidating the molecular pathways through which BRCA1 and BRCA2 operate, we aim to provide insights into their pivotal roles in maintaining genomic integrity and their implications for cancer treatment.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"150 ","pages":"Article 103847"},"PeriodicalIF":3.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947293","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

Emerging connections: Poly(ADP-ribose), FET proteins and RNA in the regulation of DNA damage condensates 新出现的联系：聚（adp -核糖），FET蛋白和RNA在DNA损伤凝聚体的调节

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-08 DOI: 10.1016/j.dnarep.2025.103846

Silvia Lombardi, Mara Zilocchi, Roland Nicsanu, Silvia Maria Luisa Barabino

{"title":"Emerging connections: Poly(ADP-ribose), FET proteins and RNA in the regulation of DNA damage condensates","authors":"Silvia Lombardi, Mara Zilocchi, Roland Nicsanu, Silvia Maria Luisa Barabino","doi":"10.1016/j.dnarep.2025.103846","DOIUrl":"10.1016/j.dnarep.2025.103846","url":null,"abstract":"<div><div>Our genome is exposed to thousands of DNA lesions every day, posing a significant threat to cellular viability. To deal with these lesions, cells have evolved sophisticated repair mechanisms collectively known as the DNA damage response. DNA double-strand breaks (DSBs) are very cytotoxic damages, and their repair requires the precise and coordinated recruitment of multiple repair factors to form nuclear <em>foci</em>. Recent research highlighted that these repair structures behave as biomolecular condensates, <em>i.e.</em> membraneless compartments with liquid-like properties. The formation of condensates is driven by weak, multivalent interactions among proteins and nucleic acids, and recent studies highlighted the roles of poly(ADP-ribose) (PAR) and RNA in regulating DSBs-related condensates. Additionally, the FET family of RNA-binding proteins (including FUS, EWS and TAF15), has emerged as a critical player in the DNA damage response, with recent evidence suggesting that FET proteins support the formation and dynamics of repair condensates. Notably, phase separation of FET proteins is implicated also in their pathological functions in cancer biology, highlighting the pervasive role of condensation. This review will provide an overview of biomolecular condensates at DSBs, focusing on the interplay among PAR and RNA in the spatiotemporal regulation of FET proteins at repair complexes. We will also discuss the role of FET condensates in cancer biology and how they are targeted for therapeutic purposes. The study of biomolecular condensates holds great promise for advancing our understanding of key cellular processes and developing novel therapeutic strategies, but requires careful consideration of potential challenges.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"150 ","pages":"Article 103846"},"PeriodicalIF":3.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144068527","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

Targeting base excision repair in precision oncology 精准肿瘤学中靶向碱基切除修复

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 DOI: 10.1016/j.dnarep.2025.103844

Nicola P. Montaldo , Hilde Loge Nilsen , Diana L. Bordin

引用次数: 0

Joining of DNA breaks- interplay between DNA ligases and poly (ADP-ribose) polymerases DNA断裂的连接- DNA连接酶和多聚核糖聚合酶之间的相互作用

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 DOI: 10.1016/j.dnarep.2025.103843

Nicolas Call, Alan E. Tomkinson

{"title":"Joining of DNA breaks- interplay between DNA ligases and poly (ADP-ribose) polymerases","authors":"Nicolas Call, Alan E. Tomkinson","doi":"10.1016/j.dnarep.2025.103843","DOIUrl":"10.1016/j.dnarep.2025.103843","url":null,"abstract":"<div><div>The joining of DNA single- and double-strand breaks (SSB and DSB) is essential for maintaining genome stability and integrity. While this is ultimately accomplished in human cells by the DNA ligases encoded by the <em>LIG1</em>, <em>LIG3</em> and <em>LIG4</em> genes, these enzymes are recruited to DNA breaks through specific interactions with proteins involved in break sensing and recognition and/or break processing. In this review, we focus on the interplay between the DNA break-activated poly (ADP-ribose) polymerases, PARP1 and PARP2, poly (ADP-ribose) (PAR) and the DNA ligases in DNA replication and repair. The most extensively studied example of this interplay is the recruitment of DNA ligase IIIα (LigIIIα) and other repair proteins to SSBs through an interaction between XRCC1, a scaffold protein and partner protein of nuclear LigIIIα, and PAR synthesized by PARP1 and to a lesser extent PARP2. Recently, these proteins have been implicated in a back-up pathway for joining Okazaki fragments that appears to have a critical function even in cells with no defect in the major LigI-dependent pathway. Finally, we discuss the effects of FDA-approved PARP1/2 inhibitors on DNA replication and repair in cancer and non-malignant cells and the potential utility of DNA ligase inhibitors as cancer therapeutics.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103843"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923468","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

Weaponizing CRISPR/Cas9 for selective elimination of cells with an aberrant genome 武器化CRISPR/Cas9选择性消除具有异常基因组的细胞

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 DOI: 10.1016/j.dnarep.2025.103840

Sara Tavella , Alessia di Lillo , Anastasia Conti , Fabio Iannelli , Alexandra Mancheno-Ferris , Valentina Matti , Raffaella Di Micco , Fabrizio d’Adda di Fagagna

{"title":"Weaponizing CRISPR/Cas9 for selective elimination of cells with an aberrant genome","authors":"Sara Tavella , Alessia di Lillo , Anastasia Conti , Fabio Iannelli , Alexandra Mancheno-Ferris , Valentina Matti , Raffaella Di Micco , Fabrizio d’Adda di Fagagna","doi":"10.1016/j.dnarep.2025.103840","DOIUrl":"10.1016/j.dnarep.2025.103840","url":null,"abstract":"<div><div>The CRISPR/Cas9 technology is a powerful and versatile tool to disrupt genes’ functions by introducing sequence-specific DNA double-strand breaks (DSBs). Here, we repurpose this technology to eradicate aberrant cells by specifically targeting silent and non-functional genomic sequences present only in target cells to be eliminated. Indeed, an intrinsic challenge of most current therapies against cancer and viral infections is the non-specific toxicity that they can induce in normal tissues because of their impact on important cellular mechanisms shared, to different extents, between unhealthy and healthy cells. The CRISPR/Cas9 technology has potential to overcome this limitation; however, so far effectiveness of these approaches was made dependent on the targeting and inactivation of a functional gene product. Here, we generate proof-of-principle evidence by engineering HeLa and RKO cells with a promoterless Green Fluorescent Protein (GFP) construct. The integration of this construct simulates either a genomic alteration, as in cancer cells, or a silent proviral genome. Cas9-mediated DSBs in the GFP sequence activate the DNA damage response (DDR), reduce cell viability and increase mortality. This is associated with increased cell size, multinucleation, cGAS-positive micronuclei accumulation and the activation of an inflammatory response. Pharmacological inhibition of the DNA repair factor DNA-PK enhances cell death. These results demonstrate the therapeutic potential of the CRISPR/Cas9 system in eliminating cells with an aberrant genome, regardless of the expression or the function of the target DNA sequence.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103840"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902250","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

Targeting DNA damage sensors for cancer therapy 靶向DNA损伤传感器用于癌症治疗

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 DOI: 10.1016/j.dnarep.2025.103841

Matthew R. Jordan , Pamela L. Mendoza-Munoz , Katherine S. Pawelczak , John J. Turchi

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Reversible association of ubiquitin with PCNA is important for template switching in S. cerevisiae 泛素与PCNA的可逆结合对于酿酒葡萄球菌的模板转换是重要的

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 DOI: 10.1016/j.dnarep.2025.103842

Cindy Meister, Ronald P. Wong, Zhi-Hoon Park, Helle D. Ulrich

{"title":"Reversible association of ubiquitin with PCNA is important for template switching in S. cerevisiae","authors":"Cindy Meister, Ronald P. Wong, Zhi-Hoon Park, Helle D. Ulrich","doi":"10.1016/j.dnarep.2025.103842","DOIUrl":"10.1016/j.dnarep.2025.103842","url":null,"abstract":"<div><div>Polyubiquitylation of the replication factor PCNA activates the replicative bypass of DNA lesions via an error-free pathway involving template switching. However, the mechanism by which the K63-linked polyubiquitin chains facilitate damage bypass is poorly understood. Intriguingly, stable fusions of linear ubiquitin oligomers to PCNA, designed as mimics of the native K63-linked chains, are not functional, while enzymatic modification of PCNA with linear chains supports template switching in budding yeast. To investigate the cause of this discrepancy, we have taken an alternative approach to identify the features of polyubiquitylated PCNA essential for activating damage bypass. We designed linear, non-cleavable ubiquitin constructs that can be recruited non-covalently to PCNA via a PIP motif. We found that these partially suppress the damage sensitivity and elevated spontaneous mutation rates of yeast strains defective in PCNA ubiquitylation. Genetic analysis confirms that this rescue is due to an activation of the template switching pathway. Surprisingly, even the recruitment of monoubiquitin units promotes activity in this setting. These observations suggest that the reversibility of ubiquitin’s association with PCNA is more important than the actual linkage of the polyubiquitin chain. Thus, our study highlights the dynamic nature of ubiquitin signaling in the context of DNA damage bypass.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103842"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902249","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}

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Obituary: Francis Fabre (1940–2024) 讣告：弗朗西斯·法布尔（1940-2024）

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 DOI: 10.1016/j.dnarep.2025.103838

Eric Coïc

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