Specific regulation of BACH1 by the hotspot mutant p53^R175H reveals a distinct gain-of-function mechanism.

ABSTRACT: Although the gain of function (GOF) of p53 mutants is well recognized, it remains unclear whether different p53 mutants share the same cofactors to induce GOFs. In a proteomic screen, we identified BACH1 as a cellular factor that recognizes the p53 DNA-binding domain depending on its mutation status. BACH1 strongly interacts with p53^R175H but fails to effectively bind wild-type p53 or other hotspot mutants in vivo for functional regulation. Notably, p53^R175H acts as a repressor for ferroptosis by abrogating BACH1-mediated downregulation of SLC7A11 to enhance tumor growth; conversely, p53^R175H promotes BACH1-dependent tumor metastasis by upregulating expression of pro-metastatic targets. Mechanistically, p53^R175H-mediated bidirectional regulation

SUBMITTER: Su Z 

PROVIDER: S-EPMC10320414 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature