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Updated: Apr 19, 2026

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Cancer-associated synonymous mutations reveal stress signal-dependent mRNA folding that selectively modulates protein

Sivakumar Vadivel Gnanasundram1,2, Lixiao Wang3, Sa Chen3

  • 1Department of Medical Biosciences, Umea University, Umea 90185, Sweden robin.fahraeus@inserm.fr sivavg@iitpkd.ac.in.

RNA (New York, N.Y.)
|April 17, 2026
PubMed

Insights

Cancer-associated synonymous mutations disrupt DNA damage-induced TP53 mRNA folding, altering p53 protein activity and gene expression. These mutations highlight a mechanism where mRNA structure influences protein function.

Area of Science:

  • Molecular Biology
  • Cancer Genomics
  • RNA Structure

Background:

  • Technical advances enable studying mRNA structure changes in response to signaling pathways.
  • The impact of mRNA structure on encoded protein function is not well understood.

Purpose of the Study:

  • Investigate how cancer-associated synonymous mutations (CASMs) affect TP53 mRNA structure and p53 protein function.
  • Determine if CASMs interfere with signal-induced mRNA folding and subsequent protein activity.

Main Methods:

  • In-cell RNA structural probing (SHAPE-MaP) to analyze mRNA folding.
  • Transcript and chromatin immunoprecipitation (ChIP) analysis.
  • Transcriptome analysis.

Main Results:

  • Two CASMs (c.102 C>A and c.102 C>G) prevent DNA damage-induced TP53 mRNA folding.
  • p53 from CASM34 exhibits reduced promoter binding and selective downstream gene induction (PUMA, 14-3-3-σ, but not p21CDKN1A).
  • CASM34 globally attenuates DNA damage-responsive gene expression.

Conclusions:

  • CASM34 interferes with signal-induced p53 mRNA folding during DNA damage, selectively modulating p53 activity.
  • Cancer-associated synonymous mutations can target signal-induced mRNA structures to influence protein function.
Keywords:
DNA damage responseRNA structuresp53synonymous cancer mutation

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