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)