Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations

Nature Genetics, Год журнала: 2025, Номер 57(1), С. 140 - 153

Опубликована: Янв. 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.

Язык: Английский

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The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations

Biomolecules, Год журнала: 2025, Номер 15(2), С. 244 - 244

Опубликована: Фев. 8, 2025

Mutations in the TP53 gene and chromosomal instability (CIN) are two of most common alterations cancer. CIN, marked by changes chromosome numbers structure, drives tumor development, but is poorly tolerated healthy cells, where developmental tissue homeostasis mechanisms typically eliminate cells with abnormalities. Mechanisms that allow cancer to acquire adapt CIN remain largely unknown. Tumor suppressor protein p53, often referred as “guardian genome”, plays a critical role maintaining genomic stability. In cancer, strongly correlates mutations, recent studies suggest p53 prevents propagation abnormal karyotypes arising from mitotic errors. Furthermore, dysfunction frequent underwent whole-genome doubling (WGD), process facilitates onset, promotes aneuploidy tolerance, associated poor patient prognosis across multiple types. This review summarizes current insights into p53’s protecting copy number discusses implications its for adaption cells.

Язык: Английский

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Lipidome atlas of p53 mutant variants in pancreatic cancer

Biology Direct, Год журнала: 2025, Номер 20(1)

Опубликована: Апрель 11, 2025

Язык: Английский

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Selective metabolic regulations by p53 mutant variants in pancreatic cancer

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Ноя. 26, 2024

Approximately half of all human cancers harbour mutations in the p53 gene, leading to generation neomorphic mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, clinical significance GOF mutations, as well selectivity individual variants, remains controversial and unclear.

Язык: Английский

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Vaccines targeting p53 mutants elicit anti-tumor immunity

Cancer Letters, Год журнала: 2024, Номер unknown, С. 217421 - 217421

Опубликована: Дек. 1, 2024

Язык: Английский

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