Genomics

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Genome-wide binding of wild-type p53 and R248Q missense mutant variants in isogenic human acute myeloid leukemia (AML) cell lines


ABSTRACT: TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). The precise functional and molecular mechanisms of the DNE have remained elusive. Using a variety of novel model systems including CRISPR-edited human isogenic cell lines, transcriptional reporter cell lines, and targeted protein degradation assays combined with functional and molecular analyses we functionally characterize the DNE and demonstrate that formation of heterotetramers between R248Q and WT p53 impairs proper WT p53 functionality by preventing DNA binding and subsequent target gene transactivation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284299 | GEO | 2025/03/14

REPOSITORIES: GEO

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