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Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP2]

ABSTRACT: Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP2]

PROVIDER: PRJNA940109 | ENA |

REPOSITORIES: ENA

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Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death

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Project description:Mutations that occur within the oligomerization domain (OD) of the tumor suppressor p53 generally abolish p53 tetramerization and are associated with increased cancer susceptibility in Li-Fraumeni syndrome (LFS). Despite their prevalence, the impact of OD-mutant p53 proteins in cancer, especially beyond a loss of canonical p53 activity, has not been well elucidated. We sought to delineate the gain-of-function (GOF) vs. loss-of-function (LOF) activities of OD-mutant p53, specifically focusing on the LFS tumor-derived p53(A347D) variant. We obtained LFS patient-derived dermal fibroblasts heterozygous for the mutation and generated an allelic series of U2OS cancer cell lines expressing wild-type p53, heterozygous (p53+/AD) or homozygous (p53AD/AD) mutant p53 or no p53 (p53 KO). In contrast to wild-type p53, mutant p53(A347D) exclusively forms dimers in both fibroblasts and cancer cells and has lost the ability to bind and transactivate the majority of canonical p53 target genes, which yields comparable tumorigenic properties between mutant p53 and p53 KO cells. Mutant p53(A347D), however, displays neomorphic activities. Glycolysis and oxidative phosphorylation pathways are enriched in cells bearing p53(A347D) relative to both wild-type p53 and p53 KO cells. Furthermore, dimeric mutant p53 induces striking mitochondrial network aberration and preferentially associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Ultimately, we describe dimeric mutant p53 as wielding a double-edged sword: driving tumorigenesis through LOF while gaining enhanced apoptogenic activity, thereby providing a potential basis for select therapeutic approaches.

2023-04-20 | GSE226406 | GEO

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A MUTATION IN THE POT1 GENE IS RESPONSIBLE FOR CARDIAC ANGIOSARCOMA IN TP53-NEGATIVE LI-FRAUMENI-LIKE FAMILIES

Project description:Whole Exome sequencing of two patients with Cardiac angiosarcoma in Li-Fraumeni-like families discovers that a mutation in the pot1 gene is responsible for cardiac angiosarcoma in tp53-negative li-fraumeni-like families

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Project description:Germline Hemizygous Deletion of CDKN2A-CDKN2B Locus in a Patient Presenting with Li-Fraumeni Syndrome

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