FAM193A is a positive regulator of p53 activity

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112230
• Main Authors: Szwarc, Maria M., Guarnieri, Anna L., Joshi, Molishree, Duc, Huy N., Laird, Madison C., Pandey, Ahwan, Khanal, Santosh, Dohm, Emily, Bui, Aimee K., Sullivan, Kelly D., Galbraith, Matthew D., Andrysik, Zdenek, Espinosa, Joaquin M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2023; Elsevier
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Cell Cycle Proteins - metabolism; Cell Line, Tumor; cell-cycle arrest; CP: Cancer; CP: Molecular biology; CRISPR; Humans; MDM2; MDM4; MDMX; Neoplasms - pathology; Nutlin; p53; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2 - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; CRISPR; cell-cycle arrest; Nutlin; MDMX; CP: Cancer; MDM2; CP: Molecular biology; apoptosis; MDM4; p53
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112230

Inactivation of the p53 tumor suppressor, either by mutations or through hyperactivation of repressors such as MDM2 and MDM4, is a hallmark of cancer. Although many inhibitors of the p53-MDM2/4 interaction have been developed, such as Nutlin, their therapeutic value is limited by highly heterogeneous cellular responses. We report here a multi-omics investigation of the cellular response to MDM2/4 inhibitors, leading to identification of FAM193A as a widespread regulator of p53 function. CRISPR screening identified FAM193A as necessary for the response to Nutlin. FAM193A expression correlates with Nutlin sensitivity across hundreds of cell lines. Furthermore, genetic codependency data highlight FAM193A as a component of the p53 pathway across diverse tumor types. Mechanistically, FAM193A interacts with MDM4, and FAM193A depletion stabilizes MDM4 and inhibits the p53 transcriptional program. Last, FAM193A expression is associated with better prognosis in multiple malignancies. Altogether, these results identify FAM193A as a positive regulator of p53. [Display omitted] •A CRISPR screen identifies FAM193A as required for the response to MDM2 inhibition•FAM193A is necessary for p53 stabilization and downstream transcriptional responses•FAM193A interacts with the RING domain of MDM4 and destabilizes MDM4•FAM193A expression is associated with better prognosis in multiple cancer types Szwarc et al. identify FAM193A as a positive regulator of the tumor suppressor p53. Using genetic screening, FAM193A is found to be required for the cellular response to targeted p53 activation. FAM193A interacts with the p53 repressors MDM2 and MDM4, destabilizes MDM4, and enhances p53 activity as a transcription factor.