The Prolonged Half-Life of the p53 Missense Variant R248Q Promotes Accumulation and Heterotetramer Formation with Wild-Type p53 to Exert the Dominant-Negative Effect.

ABSTRACT: Missense mutants of p53, such as the frequent hotspot variant R248Q, exert a dominant-negative effect (DNE) on wild-type (WT) p53 in cancer cells with monoallelic TP53 mutations. However, the precise functional and molecular mechanisms of the DNE have remained elusive due to a lack of appropriate model systems. In this study, we developed a variety of model systems, including CRISPR-edited human isogenic cell lines and transcriptional reporter cell lines, and targeted protein degradation assays that were combined with functional and molecular analyses to functionally characterize the DNE. Formation of heterotetramers between R248Q and WT p53 impaired proper WT p53 functionality by preventing DNA binding and subsequent target gene transactivation. Furthermore, the markedly increased protein

SUBMITTER: Klemm N 

PROVIDER: S-EPMC12127799 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature