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RNA riboswitch structures control prokaryotic gene expression in response to changes in the cellular environment, but how this concept has evolved in mammalian cells is yet little known. Here, we describe the riboswitch-like features of the p53 mRNA that controls p53 synthesis following DNA damage. The conserved BOX-I stem-loop in the 5′ coding sequence acts as an aptamer that controls the folding of a compact downstream MDM2-binding p53 mRNA structure. MDM2 brings the p53 mRNA to the ribosome and promotes p53 synthesis. High-throughput in-cell RNA structural probing and in vitro RNA-RNA and RNA-protein interactions show how the cancer-associated synonymous mutation in codon 22 (CASM22) of the BOX-I aptamer stabilizes the p53 mRNA structure and prevents the formation of the MDM2-binding platform. However, the CASM22 does not affect p53 mRNA folding during the unfolded protein response, demonstrating the specificity by which the CASM22 targets the p53 DNA damage response.