AI Article Synopsis
- Mutations in the BRCA1 gene significantly increase the risk of breast and ovarian cancers due to its role in maintaining genomic stability.
- A newly identified BRCA1 protein complex, which includes BCLAF1, is activated in response to DNA damage and regulates the splicing of pre-mRNA for genes involved in DNA repair and damage signaling.
- Disruption of this BRCA1-mRNA splicing complex leads to increased sensitivity to DNA damage and genomic instability, highlighting its critical role in the cellular response to DNA damage.
Article Abstract
Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017265 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2014.03.021 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Targeted Activation of OGG1 Inhibits Paraptosis in Lens Epithelial Cells of Early Age-Related Cortical Cataract.
Invest Ophthalmol Vis Sci
January 2025
Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China.
Purpose: To investigate potential modes of programmed cell death in the lens epithelial cells (LECs) of patients with early age-related cortical cataract (ARCC) and to explore early-stage intervention strategies.
Methods: Anterior lens capsules were collected from early ARCC patients for comprehensive analysis. Ultrastructural examination of LECs was performed using transmission electron microscopy.
A Case-Control Study of the Association Between Gene Polymorphisms (rs1695 and rs1138272) and the Susceptibility to Male Infertility in the Moroccan Population.
Genet Test Mol Biomarkers
January 2025
Laboratory of Genomics and Human Genetics, 1, Place Louis Pasteur, Institut Pasteur du Maroc, Casablanca, Morocco.
Infertility affects 10-15% of couples worldwide, with male factors accounting for half of cases. Environmental, behavioral, and genetic problems contribute to spermatogenic failure in 30% of idiopathic male infertility cases. Other factors, such as oxidative stress (OS), cause impaired spermatogenesis, abnormal sperm morphology, and reduced motility, eventually triggering male infertility.
View Article and Find Full Text PDFEnhancement Of High-Dose Chemotherapy and Autologous SCT with the PARP Inhibitor Olaparib for Refractory Lymphoma.
Clin Cancer Res
January 2025
The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Purpose: More active high-dose chemotherapy (HDC) regimens are needed for autologous stem-cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a poly(ADP-ribose) polymerase (PARP) inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT.
View Article and Find Full Text PDFLoss of HNRNPK During Cell Senescence Linked to Reduced Production of CDC20.
Mol Cell Biol
January 2025
Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA.
Cellular senescence is a complex biological response to sublethal damage. The RNA-binding protein HNRNPK was previously found to decrease prominently during senescence in human diploid fibroblasts. Here, analysis of the mechanisms leading to reduced HNRNPK abundance revealed that in cells undergoing senescence, mRNA levels declined transcriptionally and full-length HNRNPK protein was progressively lost, while the abundance of a truncated HNRNPK increased.
View Article and Find Full Text PDFDiscovery of WDR5-MLL1 and HDAC Dual-Target Inhibitors for the Treatment of Acute Myeloid Leukemia.
J Med Chem
January 2025
Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Targeting the WDR5-MLL1 protein-protein interaction (PPI) is considered to be an effective approach for the treatment of MLL-rearranged leukemia. However, interfering with WDR5-MLL1 PPI reduces methylated H3K4 levels and induces a decline in acetylated H3 levels, which may contribute to the suboptimal cellular efficacy of WDR5 inhibitors. We observed that cotreatment with WDR5-MLL1 PPI and HDAC inhibitors augmented the antiproliferative effect in MV-4-11 cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!