Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations

Nature Genetics, Journal Year: 2025, Volume and Issue: 57(1), P. 140 - 153

Published: Jan. 1, 2025

Abstract The mutational landscape of TP53 , a tumor suppressor mutated in about half all cancers, includes over 2,000 known missense mutations. To fully leverage mutation status for personalized medicine, thorough understanding the functional diversity these mutations is essential. We conducted deep scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 variants cancer cells. This high-resolution approach, covering 94.5% cancer-associated mutations, precisely mapped impact individual on cell fitness, surpassing previous studies distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants pharmacological reactivation. Moreover, we uncovered roles splicing alterations nonsense-mediated messenger RNA decay mutation-driven dysfunction. These findings underscore power advancing clinical variant interpretation genetic counseling therapy.

Language: Английский

TP53: the unluckiest of genes?

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Abstract The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated virtually every tumor, and second tumor this inactivation due to mutation TP53 gene. In perspective, we show that diverse mutational spectrum unique among all other cancer-associated proteins discuss what drives selection of mutations cancer. We highlight several factors conspire make protein particularly vulnerable by constantly plague our genome. appears gene has emerged as victim its own evolutionary past shaped structure function towards pluripotent suppressor, but came with an increased structural fragility DNA-binding domain. loss - associated dominant-negative effects main mechanism will impair suppressive function, regardless whether neomorphic phenotype some these variants.

Language: Английский

Small molecules that targeting p53 Y220C protein: mechanisms, structures, and clinical advances in anti-tumor therapy

Molecular Diversity, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Language: Английский