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

Autor: Palomar-Siles M; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Heldin A; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Zhang M; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Strandgren C; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Yurevych V; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., van Dinter JT; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Engels SAG; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Hofman DA; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Öhlin S; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Meineke B; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Bykov VJN; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., van Heesch S; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Wiman KG; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Klas.Wiman@ki.se.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Nov 25; Vol. 13 (11), pp. 997. Date of Electronic Publication: 2022 Nov 25.
DOI: 10.1038/s41419-022-05431-2
Abstrakt: 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).)
Databáze: MEDLINE
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