GEO series

DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop associated genome instability [CUT&Tag ]

GSE278484 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 3 samples Submitted 2026/05/21 Platform GPL24676

Summary

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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Direct links to NCBI, no account and no request form: the whole study as GSE278484_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 3 samples. Raw sequencing reads are also available from ENA.

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Also filed as BioProject PRJNA1167343 and SRA study SRP535838. Searching any of these in the dataset finder brings you back here.

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