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Results for “DNA replication checkpoint”

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24 records · Page 2Linked to original sources
PubMed2026

Functions and mechanisms of BRCA1 in early embryonic development.

Breast Cancer Gene 1 (BRCA1) is a critical regulator of genome integrity whose dysfunction greatly increases lifetime risk of breast and ovarian cancers. While BRCA1 has been extensively studied in the contexts of adult biology and cancer, its diverse functions, including homologous recombination-mediated DNA repair, cell cycle checkpoint activation, protein ubiquitination, and transcriptional regulation, have many underexplored implications. In early embryonic development, the maternal-to-zygotic transition (MZT) and subsequent developmental processes place extraordinary demands on DNA replication fidelity, cell cycle regulation, transcriptional activation, and chromatin remodeling. These critical processes overlap strikingly with canonical functions of BRCA1, yet its function in early development is poorly characterized. In this review, we investigate BRCA1 conservation across species and connect its well-established functions to findings from developmental studies to assess its role in development. We highlight evidence of BRCA1 mitigating genome integrity loss from diverse sources, maintaining the proliferative activity needed for successful germ layer formation and early tissue morphogenesis, and regulating transcription and epigenetic modifications. Together, this synthesis supports a model where BRCA1 acts as a multi-functional and dynamic regulator of early embryogenesis. Building on this, we propose outstanding questions that could further illuminate these developmental roles. Characterization of BRCA1 in early development may not only provide important insight into the origin and progression of cancer susceptibility but may also elucidate fundamental mechanisms shaping early development.

BRCA1 Protein↗
PubMed2025

Modulation of Cell Cycle Kinases by Kaposi's Sarcoma-Associated Herpesvirus.

The cell cycle is governed by kinase activity that coordinates progression through a series of regulatory checkpoints, preventing the division of damaged cells. The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes multiple genes that modulate or co-opt the activity of these kinases, shaping the cellular environment to promote viral persistence. By advancing the cell cycle, KSHV facilitates latent replication and subsequent transmission of viral genomes to daughter cells, while also contributing to the establishment of multiple cancer types. Conversely, during viral lytic replication, KSHV extends the resting phase of the cell cycle to prevent cellular DNA synthesis that would otherwise compete for essential replication precursors. This review will examine the mechanisms KSHV has evolved to control the kinase activity regulating host cell cycle progression.

Herpesvirus 8, Human↗
PubMed2026

An overview of the DNA damage response in female reproductive system and breast cancers: A narrative review.

The DNA damage response (DDR) is a fundamental cellular network that preserves genomic integrity, and its dysregulation drives initiation, progression, and therapeutic response in female reproductive system and breast cancers. This narrative review provides a comparative analysis of DDR alterations across ovarian, endometrial, cervical, and breast cancers, synthesizing molecular studies, clinical trials, and international guidelines from PubMed/MEDLINE, Scopus, and Web of Science. DDR alterations vary substantially among these cancers, reflecting differences in tissue origin, hormonal regulation, and viral oncogenesis. Homologous recombination repair defects, particularly in breast cancer susceptibility 1/2, partner and localizer of BRCA2, ataxia telangiectasia mutated, and checkpoint kinase 2), are prevalent in ovarian, endometrial, and breast cancers, predicting sensitivity to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors. In endometrial cancer, homologous recombination deficiency predominates in high-grade tumor protein p53-mutated subtypes, while Fanconi anemia pathway alterations characterize aggressive serous carcinomas. Cervical cancer exhibits virus-induced DDR disruption and replication stress. Quantitative biomarkers, including tumor mutational burden, microsatellite instability, Radiation sensitive 51, Fanconi anemia complementation group D2, excision repair cross-complementation group 1, and DDR-related microRNAs enable patient stratification. Emerging ataxia telangiectasia and Rad3-related and WEE1 inhibitors show promise in combination regimens. Understanding of tumor-specific DDR enables rational therapeutic stratification, providing a framework for precision oncology.

DNA damage response, Ovarian neoplasms, Endometria↗
PubMed2026

The clinical landscape of POLE-mutant colorectal cancer: a retrospective analysis of real-world outcome.

BACKGROUND: Pathogenic mutations in the POLE gene disrupt its proofreading function during DNA replication, causing an accumulation of erroneous nucleotide incorporations. This defect leads to a significantly elevated tumor mutation burden (TMB) and increased generation of tumor neoantigens. These molecular characteristics suggest a potential association between POLE-mutant tumors and distinct prognostic outcomes in colorectal cancer (CRC); however, clinical evidence supporting this correlation remains limited. METHODS: We retrospectively collected a cohort of CRC patients harboring pathogenic POLE mutations. Comparative analyses were performed between POLE-mutant and POLE wild-type CRCs regarding their clinical characteristics, prognostic outcomes, and genomic profiles. Additionally, we evaluated the response to immunotherapy in metastatic POLE-mutant CRC cases. RESULTS: Among 35,108 CRC patients, pathogenic POLE mutations were identified in 261 individuals, accounting for 0.74% of the cohort. The median age at diagnosis for POLE-mutant patients was 48 years, with a male predominance (74.4%) and a substantial proportion (50.4%) of tumors localized in the right-sided colon. All patients with pathogenic POLE mutations exhibited hypermutated phenotypes, characterized by a median TMB of 235.26 mutations per megabase (range: 71.20-719.00 mutations/Mb). In stage II CRC, POLE mutations were significantly associated with a reduced risk of recurrence (hazard ratio [HR] 0.344, 95% confidence interval [CI] 0.157-0.754, p = 0.008) when compared to POLE wild-type, microsatellite stable CRC patients. However, this association was not evident in stage III patients (HR 1.004, 95% CI 0.490-2.057, p = 0.992). Importantly, the incorporation of immune checkpoint inhibitors in first-line treatment regimens significantly improved progression-free survival (HR = 0.247, 95% CI 0.117-0.552, p = 0.0002) and overall survival (HR = 0.317, 95% CI 0.103-1.143, p = 0.0832) in metastatic CRC patients with pathogenic POLE mutations. CONCLUSIONS: Pathogenic POLE-mutant CRC constitutes a relatively rare, yet clinically important, subtype. These cancers exhibit distinct clinicopathological and genomic features. Our results indicate that mutations in the POLE gene may serve as a valuable prognostic marker and a potential indicator of benefit to immunotherapy in CRC, offering promising avenues for personalized treatment strategies.

Humans↗
PubMed2026

Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care.

A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occasionally oncogenes. In most hereditary cancer syndromes, Knudson's two-hit hypothesis applies, where a second somatic event inactivates the remaining allele of a tumor suppressor or DNA repair gene, leading to tumorigenesis. Advancements in genome-wide sequencing have significantly enhanced our understanding of the mutational processes involved in hereditary cancers. In particular, the assessment of microsatellite instability (MSI), tumor mutational burden (TMB), and mutational signatures has emerged as a powerful tool for the identification of hereditary tumors. Tumors with high or ultra-high TMB often reflect underlying DNA repair deficiencies, while specific mutational signatures can pinpoint the defective pathway. These tumor mutational features are especially informative in syndromes involving mismatch repair (MMR), homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and polymerase proofreading. Moreover, tumor sequencing aids in the interpretation of germline variants, identifies somatic mosaicism, and helps differentiate hereditary from sporadic cancers. Additionally, tumor molecular features associated with DNA repair deficiencies offer insights into personalized therapies, such as the use of PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for MMR- and polymerase proofreading-deficient cancers. Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer.

Humans↗
PubMed2005

Inactivation of the pre-mRNA cleavage and polyadenylation factor Pfs2 in fission yeast causes lethal cell cycle defects.

Faithful chromosome segregation is fundamentally important for the maintenance of genome integrity and ploidy. By isolating conditional mutants defective in chromosome segregation in the fission yeast Schizosaccharomyces pombe, we identified a role for the essential gene pfs2 in chromosome dynamics. In the absence of functional Pfs2, chromosomal attachment to the mitotic spindle was defective, with consequent chromosome missegregation. Under these circumstances, multiple intracellular foci of spindle checkpoint proteins Bub1 and Mad2 were seen, and deletion of bub1 exacerbated the mitotic defects and the loss of cell viability that resulted from the loss of pfs2 function. Progression from G1 into S phase following release from nitrogen starvation also required pfs2+ function. The product of the orthologous Saccharomyces cerevisiae gene PFS2 is a component of a multiprotein complex required for 3'-end cleavage and polyadenylation of pre-mRNAs and, in keeping with the conservation of this essential function, an S. pombe pfs2 mutant was defective in mRNA 3'-end processing. Mutations in pfs2 were suppressed by overexpression of the putative mRNA 3'-end cleavage factor Cft1. These data suggest unexpected links between mRNA 3'-end processing and chromosome replication and segregation.

Carrier Proteins↗