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DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability
Fanfan Li1, Ke Fang1, Shuhan Si1
1Department of Hematology, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Zhongda Hospital, Southeast University, Nanjing, China.
Background:
Mutations in the tumor suppressor p53 are among the most frequent events in human cancers. Mutant p53 acquires oncogenic activities beyond the loss of tumor suppressive function. However, how different mutation subtypes differ in their contributions to tumorigenesis remains incompletely understood.
Results:
Through pan-cancer TCGA analysis, we find that patients with p53 DNA contact mutations exhibit worse clinical outcomes than those carrying conformational mutations. Mechanistically, we demonstrate that the DNA contact mutation p53-R273H forms aberrant condensates that sequester BRCA2 and displace it from chromatin, leading to R-loop accumulation and genomic instability. We further identify the DEAD-box helicase DDX3X as a critical factor required for BRCA2-dependent R-loop resolution. Pharmacological inhibition of DDX3X with RK-33 synergizes with the PARP inhibitor Olaparib, enhancing therapeutic efficacy in p53 DNA contact mutant cancer cells.
Conclusions:
Our study establishes a pathogenic axis through which the clinically aggressive p53 DNA contact mutations drive genomic instability by dislodging BRCA2 from chromatin and disrupting R-loop homeostasis. These findings suggest a potential therapeutic avenue for treating cancers harboring high-risk p53 DNA contact mutations.
Insights
Specific p53 mutations, termed DNA contact mutations, drive cancer genomic instability by disrupting BRCA2 and R-loop homeostasis. This discovery suggests new therapeutic strategies for aggressive cancers.
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.
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