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Translational readt...
Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine
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- Palomar-Siles, M (author)
- Karolinska Institutet
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- Heldin, A (author)
- Karolinska Institutet
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Zhang, MQZ (author)
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- Strandgren, C (author)
- Karolinska Institutet
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Yurevych, V (author)
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van Dinter, JT (author)
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Engels, SAG (author)
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Hofman, DA (author)
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- Ohlin, S (author)
- Karolinska Institutet
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- Meineke, B (author)
- Karolinska Institutet
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Bykov, VJN (author)
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van Heesch, S (author)
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- Wiman, KG (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2022-11-25
- 2022
- English.
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In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 13:11, s. 997-
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Abstract
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- 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.
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- By the author/editor
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Palomar-Siles, M
-
Heldin, A
-
Zhang, MQZ
-
Strandgren, C
-
Yurevych, V
-
van Dinter, JT
-
show more...
-
Engels, SAG
-
Hofman, DA
-
Ohlin, S
-
Meineke, B
-
Bykov, VJN
-
van Heesch, S
-
Wiman, KG
-
show less...
- Articles in the publication
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Cell death & dis ...
- By the university
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Karolinska Institutet