MiR-1245 induce genomic instability
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE26715 | GEO | 2011/03/24
SECONDARY ACCESSION(S): PRJNA136359
REPOSITORIES: GEO
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Project description:This experiment is design to evaluate genomic alteration following stably expression of miR-1245, stably knock down of BRCA2 is setup as a positive control Primary normal breast epithelial cells (NBEC) were collected from the mammoplasty material of a 30-year-old woman at the Department of Plastic Surgery, the First Affiliated Hospital of Sun Yat-sen University (P. R. China), in accordance with rules and regulations concerning ethical issues on research use of human subjects in China, and were cultured in the Keratinocyte serum-free medium (Invitrogen, Carlsbad, CA) supplemented with epithelial growth factor, bovine pituitary extract and antibiotics (120 µg/mL streptomycin and 120 µg/mL penicillin). NBEC were infected with virus produced from retro vector pMSCV-miR1245 or empty pMSCV vector; or pSuper Retro BRCA2 shRNA, or pSuper Retro empty vector. After 2 days infection and 3 days culture, genomic DNA was isolated using the QIAamp DNA Mini Kit (QIAGENE, Valencia, CA). CGH microarray hybridization, data generation and normalization were performed in Shanghai Biochip Corporation.
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Project description:Accumulating evidence underscores the role of p53 mutations in inducing genomic instability, yet the underlying mechanisms remain largely elusive. Our study reveals that the p53-R273H mutation leads to the accumulation of R-loops. Specifically, p53-R273H forms abnormal condensates with BRCA2, impairing the chromatin binding of BRCA2, thereby inhibiting R-loop resolution and contributing to genomic instability. Furthermore, we have identified DDX3X as a pivotal downstream effector in the p53-BRCA2 pathway, responsible for dissolving R-loops. Notably, the strategic combination of a DDX3X inhibitor with a PARP inhibitor exhibits a potent synergistic effect, enhancing the sensitivity of cancer cell lines harboring the p53-R273H mutation. These findings uncover exploitable vulnerabilities in tumors carrying this specific p53 mutation, presenting promising opportunities for targeted therapeutic intervention.
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