Datasets

Title	5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (Ribo-Seq)
Organism
Number of Samples	24
Release Date	2022/02/14 00:00
Sequencing Types
Protocol Details

Title
Authors	Palomar-Siles M, Heldin A, Zhang M, Strandgren C, Yurevych V, van Dinter JT, Engels SAG, Hofman DA, Öhlin S, Meineke B, Bykov VJN, van Heesch S, Wiman KG
Journal	Cell death & disease
Publication Date	2022 Nov 25
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. © 2022. The Author(s).
PMC	PMC9700717
PMID	36433934
DOI

Palomar-Siles et al. 2022 (PRJNA806946)