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Recent technical advances have facilitated studies on changes in mRNA structures in response to signaling pathways. However, whether mRNA structures can affect the function of the encoded protein remains poorly understood. In-cell RNA structural probing (SHAPE-MaP) demonstrates how two cancer-associated synonymous mutations (CASMs) at proline codon 34 (c.102 C > A and c.102 C > G) prevent DNA damage–induced TP53 mRNA folding, whereas the non-cancer-asso-ciated c.102 C > U mutation does not. Transcript and chromatin immunoprecipitation (ChIP) analysis reveal that p53 expressed from CASM34 has reduced promoter binding and reduced induction of p53 downstream target genes PUMA and 14-3-3-σ, but not p21CDKN1A. Transcriptome analysis reveals a CASM34-mediated global attenuation of DNA dam-age–responsive gene expression. Together, the results demonstrate that CASM34 interferes with signal-induced p53 mRNA folding during DNA damage, leading to selective modulation of p53 protein activity. More broadly, our findings highlight a general concept by which cancer-associated synonymous mutations target signal-induced mRNA structures that influence the encoded protein.