Mutant p53 regulates a distinct gene set by a mode of genome occupancy that is shared with wild type

作者：Ramy Rahmé, L. Resnick-Silverman, Vincent Anguiano, Moray J. Campbell, P. Fenaux, J. Manfredi · 发表于：EMBO Reports · 年份：2025 · DOI：10.1038/s44319-025-00375-y · 被引用次数：2 · 研究领域：Medicine

To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53-mediated gene expression. In contrast to a dominant-negative or inhibitory role, the presence of either mutant p53 or Mdm2 actually enhances the occupancy of wild type p53 on many canonical targets. The C-terminal 19 amino acids of wild type p53 suppress the p53 response allowing for survival at sublethal doses of radiation. Further, the p53 mutant 172H is shown to occupy genes and regulate their expression via non-canonical means that are shared with wild type p53. This results in the heterozygous 172H/+ genotype having an expanded transcriptome compared to wild type p53 + /+. This study presents an integrated RNA-seq and ChIP-seq analysis after in vivo whole-body radiation of isogenically matched mouse strains. Mutant 172H p53 is shown to occupy genes and regulate their expression via non-canonical means that are shared with wild type p53. Mutant p53 and Mdm2 inhibit only a subset of wild type p53 targets in a manner independent of gene occupancy. The C-terminal 19 amino acids of wild type p53 suppress the p53 response at sublethal doses of radiation. The heterozygous 172H/+ genotype has...