Multi-Layered 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, Y220C) on gene dosage fluctuations. We observe a discrepancy in gene expression changes between wild-type and mutant p53, attributed to extensive translational and post-translational buffering mechanisms. These mechanisms effectively counterbalance transcriptional noise, stabilizing protein levels. Moreover, we demonstrate that the relative contributions of transcription, translation efficiency, and protein stability collectively shaping the final protein abundance in the context of p53 mutations. Clinical proteomic analysis of platinum-refractory ovarian cancer tissues reveals tumor-specific factors and acquired resistance pathways linked to p53 mutations. Our findings elucidate the multi-layered regulatory landscape of p53 mutations and identify potential risk factors for platinum resistance associated with these mutations.