Cancer-associated synonymous mutations target mRNA structures and protein activity.

The role of adaptive mRNA structures in regulating gene expression in mammalian cells remains poorly understood. Synonymous mutations have been linked to a range of diseases, including cancer, yet their impact on cell biology remains largely unexplored. This opinion focuses on how cancer-associated synonymous mutations (CASMs) in the TP53 mRNA disrupt signal-induced mRNA structures and alter the activity of the encoded protein. CASM203 induces conformational changes that recapitulate those driven by PERK during the unfolded protein response, promoting expression of the p53/p47 isoform. By contrast, CASM22 and CASM34 interfere with DNA damage-induced RNA structures and affect full-length p53 activity. Together, these examples illustrate an underappreciated regulatory axis in which dynamic mRNA structures interface between upstream signalling pathways and downstream effector functions, with direct implications for tumour biology.