DNA double-strand breaks (DSBs) are repaired mainly by non-homologous end joining or homologous recombination (HR). Cell cycle stage and DNA end resection are believed to regulate the commitment to HR repair. Here we identify RNF138 as a ubiquitin E3 ligase that regulates the HR pathway. RNF138 is recruited to DNA damage sites through zinc fingers that have a strong preference for DNA with 5'- or 3'-single-stranded overhangs. RNF138 stimulates DNA end resection and promotes ATR-dependent signalling and DSB repair by HR, thereby contributing to cell survival on exposure to DSB-inducing agents. Finally, we establish that RNF138-dependent Ku removal from DNA breaks is one mechanism whereby RNF138 can promote HR. These results establish RNF138 as an important regulator of DSB repair pathway choice.
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Cancer Cell Int
December 2024
Department of Applied Chemistry, Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Puli, Taiwan.
Introduction: Chronic alcohol consumption and tobacco usage are major risk factors for esophageal squamous cell carcinoma (ESCC). Excessive tobacco and alcohol consumption lead to oxidative stress and the generation of reactive carbonyl species (RCS) which induce DNA damage and cell apoptosis. This phenomenon contributes to cell damage and carcinogenesis in various organs including ESCC.
View Article and Find Full Text PDFMol Biol (Mosk)
December 2024
Institute of Functional Genomics, Moscow State University, Moscow, 119991 Russia.
The CRISPR/Cas technology of targeted genome editing made it possible to carry out genetic engineering manipulations with eukaryotic genomes with a high efficiency. Targeted induction of site-specific DNA breaks is one of the key stages of the technology. The cell repairs the breaks via one of the two pathways, nonhomologous end joining (NHEJ) and homology-driven repair (HDR).
View Article and Find Full Text PDFWorld J Surg Oncol
December 2024
Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province, P.R. China.
Background: SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly malignant primary tumor characterized by the loss of SMARCA4 expression. Despite advancements in oncology, diagnosing and treating SMARCA4-UT remain significant clinical challenges.
Case Demonstration: A 67-year-old male with a history of smoking presented to the hospital with complaints of abdominal distention and pain lasting for more than four days.
BMC Cancer
December 2024
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Background: There is increasing interest in enhancing the response of the PARP inhibitor olaparib, which is currently approved for pancreatic ductal adenocarcinoma (PDAC) patients with defects in DNA damage repair associated with germline BRCA1/2 mutations. Moreover, agents that can mimic these defects in the absence of germline BRCA1/2 mutations are an area of active research in hopes of increasing the number of patients eligible for treatment with PARP inhibitors. The extent to which regorafenib, an FDA-approved tyrosine kinase inhibitor, can be used to enhance the efficacy of PARP inhibitors in PDAC cells without known BRCA1/2 mutations remains to be investigated.
View Article and Find Full Text PDFMol Cell
December 2024
Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing 100191, China; Department of Gastrointestinal Translational Research, Peking University Cancer Hospital, Beijing 100142, China. Electronic address:
Safeguarding replication fork stability in transcriptionally active regions is crucial for precise DNA replication and mutation prevention. Here, we discover the pervasive existence of replication fork-associated RNA-DNA hybrids (RF-RDs) in transcriptionally active regions of human cells. These hybrids function as protective barriers, preventing DNA2-mediated nascent DNA degradation and replication fork collapse under replication stress.
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