Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine

Mireia Palomar-Siles, Angelos Heldin, Meiqiongzi Zhang, Charlotte Strandgren, Viktor Yurevych, Jip T van Dinter, Sem A G Engels, Damon A Hofman, Susanne Öhlin, Birthe Meineke, Vladimir J N Bykov, Sebastiaan van Heesch, Klas G Wiman

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

TP53 nonsense mutations in cancer produce truncated inactive p53 protein. We show that 5-FU metabolite 5-Fluorouridine (FUr) induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53. Ribosome profiling visualized translational readthrough at the R213X premature stop codon and demonstrated that FUr-induced readthrough is less permissive for canonical stop codon readthrough compared to aminoglycoside G418. FUr is incorporated into mRNA and can potentially base-pair with guanine, allowing insertion of Arg tRNA at the TP53 R213X UGA premature stop codon and translation of full-length wild-type p53. We confirmed that full-length p53 rescued by FUr triggers tumor cell death by apoptosis. FUr also restored full-length p53 in TP53 R213X mutant human tumor xenografts in vivo. Thus, we demonstrate a novel strategy for therapeutic rescue of nonsense mutant TP53 and suggest that FUr should be explored for treatment of patients with TP53 nonsense mutant tumors.

Original languageEnglish
Article number997
Pages (from-to)997
JournalCell Death & Disease
Volume13
Issue number11
DOIs
Publication statusPublished - Nov 2022

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