Recently, the research team led by Professors Luo Zhuojuan and Lin Chengqi from the School of Life Sciences and Technology, 91抖淫, elucidated the mechanism by which p53 DNA-contact mutations displace BRCA2 from chromatin, thereby driving R-loop accumulation and genomic instability. The findings were published online in the international academic journalGenome Biology under the title “DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability.”
Mutations in the tumor suppressor geneTP53 are the most common mutations in the human cancer genome. The p53 protein, often referred to as the “guardian of the genome,” plays a central role in regulating the cell cycle, DNA damage response, and apoptosis. Over 50% of cancer patients harbor p53 mutations, with mutation sites highly enriched in its DNA-binding domain. These mutations are primarily classified into two types: DNA-contact mutations and structural mutations. Studies have shown that different types of p53 mutants can exhibit distinct oncogenic activities and be targeted by different mechanisms. Therefore, investigating how various mutation subtypes drive tumorigenesis and developing potential therapeutic strategies based on these findings represent a core challenge in targeting p53-mutant cancers.
Through analysis of the pan-cancer TCGA database, this study revealed that patients with p53 DNA-contact mutations have a significantly poorer clinical prognosis compared to those carrying structural mutations. The research found that cells with p53 DNA-contact mutations exhibit abnormal accumulation of R-loops, which in turn leads to increased genomic instability. Mechanistic analysis indicated that p53 DNA-contact mutations form aberrant condensates; these condensates sequester BRCA2 and displace it from chromatin, triggering R-loop accumulation and genomic instability. Further investigation identified the DEAD-box helicase DDX3X as a critical factor in BRCA2-dependent R-loop accumulation. Based on the p53-mutant–BRCA2–DDX3X regulatory axis, combined treatment with Olaparib (a PARP inhibitor) and RK-33 (a DDX3X inhibitor) demonstrated a synergistic cytotoxic effect in cancer cells harboring p53 DNA-contact mutations.
In summary, this study takes the initiative in revealing the functional and molecular mechanisms by which p53 DNA-contact mutations mediate genomic instability through aberrant condensates that regulate the BRCA2–DDX3X–R-loop pathway. On this basis, the study proposes a novel therapeutic strategy of combined targeting of PARP and DDX3X, laying a critical theoretical foundation for the treatment of high-frequency, high-risk p53 DNA-contact mutant cancers that currently lack effective targeted approaches.
Li Fanfan and Fang Ke, doctoral students studying at the School of Life Sciences and Technology, 91抖淫, are the co-first authors of this paper. Prof. Luo Zhuojuan is the corresponding author. Key technical support was provided by Prof. Lin Chengqi from the School of Life Sciences and Technology, Prof. Xie Zhuoying from the School of Biological Science and Medical Engineering, and Prof. Chen Kai from the Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou). This research was funded by the National Natural Science Foundation of China, the Jiangsu Provincial Key Basic Research Program, and the Shenzhen Science and Technology Program.
Paper’s link: https://link.springer.com/article/10.1186/s13059-026-04151-6
Source: School of Life Science and Technology, 91抖淫
Translated by: Melody Zhang
Edited by: Leah Li
