IF 3 3区生物学

DNA Repair Pub Date : 2025-04-17 DOI: 10.1016/j.dnarep.2025.103839

Yaping Huang , Guo-Min Li

引用次数: 0

Identification of a novel pathogenic XPC:c.2420 + 1 G>C variant in a patient with xeroderma pigmentosum

IF 3 3区生物学

DNA Repair Pub 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":"2025-04-12","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

Corrigendum to “Role of NEIL1 in genome maintenance” [DNA Repair 148 (2025) 103820]

IF 3 3区生物学

DNA Repair Pub Date : 2025-04-09 DOI: 10.1016/j.dnarep.2025.103835

Amanda K. McCullough , Irina G. Minko , Michael M. Luzadder , Jamie T. Zuckerman , Vladimir L. Vartanian , Pawel Jaruga , Miral Dizdaroglu , R. Stephen Lloyd

引用次数: 0

Building an integrated view of R-loops, transcription, and chromatin

IF 3 3区生物学

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

Yingying Meng, Lee Zou

引用次数: 0

The differential roles of rad9 alternatively spliced forms in double- strand DNA break repair during Drosophila meiosis

IF 3 3区生物学

DNA Repair Pub Date : 2025-04-08 DOI: 10.1016/j.dnarep.2025.103833

Bareket Goldstein, Suad Sheikh-Suliman, Anna Bakhrat, Uri Abdu

{"title":"The differential roles of rad9 alternatively spliced forms in double- strand DNA break repair during Drosophila meiosis","authors":"Bareket Goldstein, Suad Sheikh-Suliman, Anna Bakhrat, Uri Abdu","doi":"10.1016/j.dnarep.2025.103833","DOIUrl":"10.1016/j.dnarep.2025.103833","url":null,"abstract":"<div><div>The 9–1–1 complex, comprising the Rad9, Hus1 and Rad1 proteins, is believed to operate as a component of a DNA damage checkpoint pathway. Our initial analysis of the <em>Drosophila hus1</em> gene showed that Hus1 plays a dual role in meiosis, regulating both meiotic DNA damage checkpoint and homologous recombination repair. In this study, we further analyzed the meiotic roles of another protein in the complex, Rad9, which has two alternatively spliced forms, Rad9A and Rad9B. Using CRISPR/Cas9, we generated flies mutant for both <em>rad9</em> isoforms. We found that, similarly to <em>hus1</em>, mutations in <em>rad9</em> lead to female sterility. Also, double-strand DNA breaks (DSBs) that form during meiosis are not processed efficiently, and the DNA within the oocyte nucleus fails to form its characteristic shape in <em>rad9</em> mutants. On the other hand, the <em>hus1</em> mutation completely disrupts checkpoint activation in DSB repair enzyme mutants, whereas the <em>rad9</em> mutation only partially impairs checkpoint activation in this context. Moreover, spatial rescue experiments revealed that Rad9B is efficient in repairing meiotic DSBs, while Rad9A is not. Furthermore, we found that female fertility in <em>rad9</em> mutants depends on early efficient meiotic DSB repair but not on karyosome formation. In summary, our results demonstrate a differential role of Rad9 alternatively spliced forms during <em>Drosophila</em> meiosis in oogenesis, and while former studies showed that Hus1 is sufficient for the effective activation of the meiotic recombination checkpoint, our results revealed that this is not true for Rad9.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"149 ","pages":"Article 103833"},"PeriodicalIF":3.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838009","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

IF 3 3区生物学

DNA Repair Pub 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":"2025-04-03","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

Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer

IF 3 3区生物学

DNA Repair Pub Date : 2025-04-03 DOI: 10.1016/j.dnarep.2025.103831

Suisui Hao , Zhaojin Liu , Heinz-Josef Lenz , Jian Yu , Lin Zhang

引用次数: 0

The replication stress response: Mechanisms and functions

IF 3 3区生物学

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

Alberto Ciccia, Alessandro Vindigni

引用次数: 0

Transport of DNA repair proteins to the cell nucleus by the classical nuclear importin pathway – a structural overview

IF 3 3区生物学

DNA Repair Pub 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":"2025-03-23","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

Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges

IF 3 3区生物学

DNA Repair Pub 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":"2025-03-16","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

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