Multilayered Regulatory Dynamics of p53 Mutations and Platinum Resistance in Ovarian Cancer.

TP53 mutation-driven gene expression programs define oncogenic phenotypes. While extensive studies have concentrated on the transcriptome and proteome, post-transcriptional processes, particularly translational variation, remain underexplored. This study presents a comprehensive analysis of the transcriptomics, translatiomics, and proteomics dynamics in the ovarian cancer cell line SKOV3, with a focus on the effects of p53 missense mutations (R175H, R273H, and Y220C) on gene dosage fluctuations. Despite clear transcriptional differences between wild-type and mutant p53, we find that extensive translational and post-translational buffering processes attenuate these discrepancies, yielding comparatively stable protein abundances. Moreover, we delineate that the relative contributions of transcription output, translation engagement, and protein stability collectively shape the final protein abundance in the context of p53 mutations. Clinical proteomic analysis of platinum-resistant ovarian cancer tissues reveals tumor-specific factors and acquired resistance pathways linked to p53 mutations. Our findings elucidate the multilayered regulatory landscape of p53 mutations and identify potential risk factors for platinum resistance associated with these mutations.