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

Sep 22, 2026

Mutations in the tumor suppressor p53 are common in human cancers, and mutant p53 can gain oncogenic functions. This study shows that p53 DNA contact mutations correlate with worse patient outcomes than conformational mutations. Mechanistically, the DNA contact mutant p53-R273H forms aberrant condensates that sequester BRCA2, displace it from chromatin, trigger R-loop accumulation, and cause genomic instability. It also identifies DDX3X as essential for BRCA2-dependent R-loop resolution. DDX3X inhibition with RK-33 synergizes with olaparib to improve efficacy in these cancer cells.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Abstract

Background

Results

Conclusions

Background

p53 mutation subtypes and clinical implications

Therapeutic gap for DNA contact mutations

Role of BRCA2 in genome integrity

Li etal. Genome Biology (2026) 27:257 [https://doi.org/10.1186/s13059-026-04151-6](https://doi.org/10.1186/s13059-026-04151-6) Genome Biology RESEARCH Open Access DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability Fanfan Li1†, Ke Fang1†, Shuhan Si1, Quanyong Zhang2,3, Menghan Fan 1, Chenghao Guo1, Jie Sun4, Zhuoying Xie4, Kai Chen3, Zhiyong Chen5, Zheng Ge1, Chengqi Lin 1,6 and Zhuojuan Luo 1* | †Fanfan Li and Ke Fang
contributed equally to this work. | | --- | | *Correspondence:
[zjluo@seu.edu.cn](zjluo@seu.edu.cn) | 1 Department of Hematology, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Zhongda Hospital, Southeast University, Nanjing, China 2 State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China 3 Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China 4 State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China 5 Functional Neurosurgery, the Affiliated Hospital of Jinan University, Guangzhou, China 6 Shenzhen Research Institute, Southeast University, Shenzhen, China Abstract 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. Keywords: p53 mutant, BRCA2, DDX3X, R-loop, Cancer Background The tumor suppressor p53, often termed the "guardian of the genome", is a master regulator of cellular homeostasis, orchestrating critical processes such as cell cycle arrest, apoptosis, and DNA damage repair [1]. Strikingly, TP53, the gene encoding p53, is the most frequently mutated gene in human cancer, with missense mutations accounting for ~ 80% of alterations [2]. These mutations are highly enriched in the DNA-binding © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory

FAQs

How do p53 DNA contact mutations differ in clinical impact from conformational mutations?

Patients carrying p53 DNA contact mutations show worse clinical outcomes than those with conformational mutations, based on pan-cancer TCGA analysis.

What mechanism links p53 DNA contact mutation to genome instability?

p53-R273H forms aberrant condensates that sequester and displace BRCA2 from chromatin, causing R-loop accumulation and genomic instability.

Why is DDX3X important, and how can it be therapeutically targeted?

DDX3X is required for BRCA2-dependent R-loop resolution. Pharmacological inhibition of DDX3X with RK-33 synergizes with the PARP inhibitor olaparib to enhance therapeutic efficacy.

Sep 22, 2026

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