DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability - PubMed
3 hours ago
- #p53 mutations
- #BRCA2
- #R-loops
- Patients with p53 DNA contact mutations, such as p53-R273H, show worse clinical outcomes compared to those with conformational mutations.
- DNA contact mutant p53 forms aberrant condensates that sequester BRCA2, displacing it from chromatin, which leads to R-loop accumulation and genomic instability.
- DDX3X, a DEAD-box helicase, is identified as crucial for BRCA2-dependent R-loop resolution.
- Pharmacological inhibition of DDX3X with RK-33 synergizes with PARP inhibitor Olaparib, enhancing therapeutic efficacy in p53 DNA contact mutant cancer cells.
- The study suggests a therapeutic avenue for cancers with high-risk p53 DNA contact mutations by targeting the BRCA2-R-loop axis.