DNA Repair最新文献_第9页

Building an integrated view of R-loops, transcription, and chromatin 构建r环、转录和染色质的综合视图

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-04-08 DOI: 10.1016/j.dnarep.2025.103832

Yingying Meng, Lee Zou

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 Epub Date: 2025-04-26 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

Stained DNA Dot Detection (SD3): An automated tool for quantifying fluorescent features along single stretched DNA molecules 染色DNA点检测（SD3）：一种自动化工具，用于定量沿单个拉伸DNA分子的荧光特征

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-04-15 DOI: 10.1016/j.dnarep.2025.103836

Obed A. Aning , Albertas Dvirnas , My Nyblom , Jens Krog , Johanna Carlson , Pegah Johansson , Tobias Ambjörnsson , Fredrik Westerlund

{"title":"Stained DNA Dot Detection (SD3): An automated tool for quantifying fluorescent features along single stretched DNA molecules","authors":"Obed A. Aning , Albertas Dvirnas , My Nyblom , Jens Krog , Johanna Carlson , Pegah Johansson , Tobias Ambjörnsson , Fredrik Westerlund","doi":"10.1016/j.dnarep.2025.103836","DOIUrl":"10.1016/j.dnarep.2025.103836","url":null,"abstract":"<div><div>The main information in DNA is its four-letter sequence that builds up the genetic information and that is traditionally read using sequencing methodologies. DNA can, however, also carry other important information, such as epigenetic marks and DNA damage. This information has recently been visualized along single DNA molecules using fluorescent labels. Quantifying fluorescent labels along DNA is done by counting the number of “dots” per length of each DNA molecule on DNA stretched on a glass surface. So far, a major challenge has been the lack of standardized data analysis tools. Focusing on DNA damage, we here present a Matlab-based automated software, Stained DNA Dot Detection (SD<sup>3</sup>), which uses a robust method for finding DNA molecules and estimating the number of dots along each molecule. We have validated SD<sup>3</sup> by comparing the outcome to manual analysis using DNA extracted from cells exposed to H<sub>2</sub>O<sub>2</sub> as a model system. Our results show that SD<sup>3</sup> achieves high accuracy and reduced analysis time relative to manual counting. SD<sup>3</sup> allows the user to define specific parameters regarding the DNA molecule and the location of dots to include during analysis via a user-friendly interface. We foresee that our open-source software can have broad use in the analysis of single DNA molecules and their modifications in research and in diagnostics.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103836"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882273","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

PARP inhibitors in ovarian cancer: Mechanisms of resistance and implications to therapy 卵巢癌中的PARP抑制剂：耐药机制及其对治疗的影响

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-04-03 DOI: 10.1016/j.dnarep.2025.103830

Sanat Kulkarni , Nethmin Seneviratne , Çağla Tosun , Srinivasan Madhusudan

{"title":"PARP inhibitors in ovarian cancer: Mechanisms of resistance and implications to therapy","authors":"Sanat Kulkarni , Nethmin Seneviratne , Çağla Tosun , Srinivasan Madhusudan","doi":"10.1016/j.dnarep.2025.103830","DOIUrl":"10.1016/j.dnarep.2025.103830","url":null,"abstract":"<div><div>Advanced epithelial ovarian cancer of the high-grade serous subtype (HGSOC) remains a significant clinical challenge due to the development of resistance to current platinum-based chemotherapies. PARP1/2 inhibitors (PARPi) exploit the well-characterised homologous recombination repair deficiency (HRD) in HGSOC and offer an effective targeted approach to treatment. Several clinical trials demonstrated that PARPi (olaparib, rucaparib, niraparib) significantly improved progression-free survival (PFS) in HGSOC in the recurrent maintenance setting. However, 40–70 % of patients develop Resistance to PARPi presenting an ongoing challenge in the clinic. Therefore, there is an unmet need for novel targeted therapies and biomarkers to identify intrinsic or acquired resistance to PARPi in ovarian cancer. Understanding the mechanisms of resistance to PARPi is crucial for identifying molecular vulnerabilities, developing effective biomarkers for patient stratification and guiding treatment decisions. Here, we summarise the current landscape of mechanisms associated with PARPi resistance such as restored homologous recombination repair functionality, replication fork stability and alterations to PARP1 and PARP2 and the DNA damage response. We highlight the role of circulating tumour DNA (ctDNA) in identifying acquired resistance biomarkers and its potential in guiding ‘real-time’ treatment decisions. Moreover, we explore other innovative treatment strategies aimed at overcoming specific resistance mechanisms, including the inhibition of ATR, WEE1 and POLQ. We also examine the role of PARPi rechallenge in patients with acquired resistance.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103830"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges 小分子调控OGG1酶活性，有前途的工具和当前的挑战

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-03-16 DOI: 10.1016/j.dnarep.2025.103827

Xavier Renaudin , Anna Campalans

{"title":"Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges","authors":"Xavier Renaudin , Anna Campalans","doi":"10.1016/j.dnarep.2025.103827","DOIUrl":"10.1016/j.dnarep.2025.103827","url":null,"abstract":"<div><div>Oxidative DNA damage, resulting from endogenous cellular processes and external sources plays a significant role in mutagenesis, cancer progression, and the pathogenesis of neurological disorders. Base Excision Repair (BER) is involved in the repair of base modifications such as oxidations or alkylations as well as single strand breaks. The DNA glycosylase OGG1, initiates the BER pathway by the recognition and excision of 8oxoG, the most common oxidative DNA lesion, in both nuclear and mitochondrial DNA. Beyond DNA repair, OGG1 modulates transcription, particularly pro-inflammatory genes, linking oxidative DNA damage to broader biological processes like inflammation and aging. In cancer therapy, BER inhibition has emerged as a promising strategy to enhance treatment efficacy. Targeting OGG1 sensitizes cells to chemotherapies, radiotherapies, and PARP inhibitors, presenting opportunities to overcome therapy resistance. Additionally, OGG1 activators hold potential in mitigating oxidative damage associated with aging and neurological disorders. This review presents the development of several inhibitors and activators of OGG1 and how they have contributed to advance our knowledge in the fundamental functions of OGG1. We also discuss the new opportunities they provide for clinical applications in treating cancer, inflammation and neurological disorders. Finally, we also highlight the challenges in targeting OGG1, particularly regarding the off-target effects recently reported for some inhibitors and how we can overcome these limitations.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103827"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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 Epub Date: 2025-04-29 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}

引用次数: 0

The replication stress response: Mechanisms and functions 复制应激反应：机制和功能

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-04-01 DOI: 10.1016/j.dnarep.2025.103834

Alberto Ciccia, Alessandro Vindigni

引用次数: 0

Identification of a novel pathogenic XPC:c.2420 + 1 G>C variant in a patient with xeroderma pigmentosum 一株新型致病性XPC的鉴定。2420 + 1 色素性干皮病患者的G>C变异

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-04-12 DOI: 10.1016/j.dnarep.2025.103837

Estu Ratnangganajati , Mukhlissul Faatih , Zulvikar Syambani Ulhaq

{"title":"Identification of a novel pathogenic XPC:c.2420 + 1 G>C variant in a patient with xeroderma pigmentosum","authors":"Estu Ratnangganajati , Mukhlissul Faatih , Zulvikar Syambani Ulhaq","doi":"10.1016/j.dnarep.2025.103837","DOIUrl":"10.1016/j.dnarep.2025.103837","url":null,"abstract":"<div><div>Xeroderma Pigmentosum group C (XP-C) is a rare, inherited autosomal recessive genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation, caused by mutations in the <em>XPC</em> gene. Among the eight XP complementation groups, XP-C is the most prevalent worldwide. Here, we present an 8-year-old girl with multiple discrete hyperpigmented and depigmented macules on her face, neck, upper chest, and arms. Her skin abnormalities first appeared around the age of one as dark patches on the face and neck, progressively worsening with sun exposure. The patient was also diagnosed with bilateral blepharoconjunctivitis and severe dry eye syndrome. Histopathological examination revealed hyperkeratinization of stratified squamous epithelium. Moreover, the proband also exhibited increased expression of PCNA, p53, and cleaved-caspase 3. Genetic analysis identified a novel homozygous pathogenic variant in the <em>XPC</em> gene at c.2420 + 1 G>C. We also demonstrated that the mutant can localize to the site of DNA damage, but it is defective in CPD repair. Among all reported intronic <em>XPC</em> variants, the <em>XPC</em>:c.2420 + 1 G>C mutation seems to have a significant impact as it results in a one-base-pair deletion at the splice donor site of exon 13. This leads to a frameshift, triggering nonsense-mediated decay and causing a premature stop codon in exon 14 of the <em>XPC</em> gene. Thus, the patient is advised to undergo regular examinations to monitor the progression of the disease and the development of precancerous lesions.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103837"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847653","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

Temporal and spatial dynamics of DNA double-strand break repair centers DNA双链断裂修复中心的时空动力学

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-03-13 DOI: 10.1016/j.dnarep.2025.103825

Junyi Chen , Wenkang Zhang , Yuqi Ma , Xueqing Yan , Yugang Wang , Qi Ouyang , Min Wu , Gen Yang

引用次数: 0

Transport of DNA repair proteins to the cell nucleus by the classical nuclear importin pathway – a structural overview DNA修复蛋白转运到细胞核的经典核输入蛋白途径-结构概述

IF 3 3区生物学

DNA Repair Pub Date : 2025-05-01 Epub Date: 2025-03-23 DOI: 10.1016/j.dnarep.2025.103828

Marcos R.M. Fontes , Fábio F. Cardoso , Bostjan Kobe

{"title":"Transport of DNA repair proteins to the cell nucleus by the classical nuclear importin pathway – a structural overview","authors":"Marcos R.M. Fontes , Fábio F. Cardoso , Bostjan Kobe","doi":"10.1016/j.dnarep.2025.103828","DOIUrl":"10.1016/j.dnarep.2025.103828","url":null,"abstract":"<div><div>DNA repair is a crucial biological process necessary to address damage caused by both endogenous and exogenous agents, with at least five major pathways recognized as central to this process. In several cancer types and other diseases, including neurodegenerative disorders, DNA repair mechanisms are often disrupted or dysregulated. Despite the diversity of these proteins and their roles, they all share the common requirement of being imported into the cell nucleus to perform their functions. Therefore, understanding the nuclear import of these proteins is essential for comprehending their roles in cellular processes. The first and best-characterized nuclear targeting signal is the classical nuclear localization sequence (NLS), recognized by importin-α (Impα). Several structural and affinity studies have been conducted on complexes formed between Impα and NLSs from DNA repair proteins, although these represent only a fraction of all known DNA repair proteins. These studies have significantly advanced our understanding of the nuclear import process of DNA repair proteins, often revealing unexpected results that challenge existing literature and computational predictions. Despite advances in computational, biochemical, and cellular assays, structural methods – particularly crystallography and in-solution biophysical approaches – continue to play a critical role in providing insights into molecular events operating in biological pathways. In this review, we aim to summarize experimental structural and affinity studies involving Impα and NLSs from DNA repair proteins, with the goal of furthering our understanding of the function of these essential proteins.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103828"},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714593","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