DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability

Area of Science:

• Oncology
• Cancer Genomics
• Molecular Biology

Background:

• Mutations in the tumor suppressor p53 are frequent in human cancers, conferring oncogenic activities beyond tumor suppression.
• The distinct roles of different p53 mutation subtypes in tumorigenesis are not fully understood.

Purpose of the Study:

• To investigate the differential impact of p53 mutation subtypes on cancer clinical outcomes.
• To elucidate the molecular mechanisms by which specific p53 mutations contribute to genomic instability.

Main Methods:

• Pan-cancer analysis of The Cancer Genome Atlas (TCGA) data.
• Mechanistic studies involving p53-R273H mutant protein, BRCA2, and R-loop dynamics.
• In vitro experiments assessing the effects of DDX3X inhibition and drug combinations.

Main Results:

• p53 DNA contact mutations are associated with worse clinical outcomes compared to conformational mutations.
• The p53-R273H mutation causes aberrant condensate formation, sequestering BRCA2 from chromatin and leading to R-loop accumulation and genomic instability.
• DDX3X is essential for R-loop resolution, and its inhibition synergizes with Olaparib to enhance therapeutic efficacy in p53 DNA contact mutant cells.

Conclusions:

• Clinically aggressive p53 DNA contact mutations promote genomic instability by displacing BRCA2 and disrupting R-loop homeostasis.
• This pathogenic axis offers a potential therapeutic target for cancers with high-risk p53 DNA contact mutations.