|
| Status |
Public on Dec 01, 2022 |
| Title |
5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (Ribo-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
The tumor suppressor gene TP53 is mutated in approximately half of all human tumors. Of those, around 10% are nonsense mutations that produce truncated and inactive p53 protein. Induction of translational readthrough is a promising approach for rescuing full-length p53 and thereby eliminate tumor cells with nonsense mutant TP53. To find novel nonsense mutant TP53 readthrough-inducing compounds with a tolerable toxicity profile, we performed an in silico screening of data at the National Cancer Institute database and identified 5-Fluorouracil (5-FU). We show here that 5-FU induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53 and that this activity is mediated by its metabolite 5-Fluorouridine (FUr). Ribo-seq analysis validated induction of translational readthrough by FUr. We also show that FUr is incorporated into RNA where it potentially allows base pairing of Arg tRNA at the R213X UGA premature termination codon. Full-length p53 rescued by FUr is transcriptionally active and triggers p53-dependent cell death. Moreover, treatment with 5-FU or FUr restores full-length p53 expression in TP53 R213X mutant human tumor xenografts in vivo. Our results suggest that induction of readthrough by 5-FU/FUr could contribute to therapeutic efficacy in patients with TP53 nonsense mutant tumors.
|
| |
|
| Overall design |
Ribo-seq analysis of readthrough in three conditions (Untreated, FUr, G418) in empty vector and R213X vector. Four replicates per group.
|
| |
|
| Contributor(s) |
Palomar-Siles M, Heldin A, Zhang M, Strandgren C, Yurevych V, van Dinter JT, Engels S, Hofman DA, Öhlin S, Meineke B, Bykov VN, van Heesch S, Wiman KG |
| Citation(s) |
36433934 |
| Submission date |
Feb 14, 2022 |
| Last update date |
Dec 01, 2022 |
| Contact name |
Sebastiaan van Heesch |
| E-mail(s) |
S.vanheesch@prinsesmaximacentrum.nl
|
| Organization name |
Princess Maxima Center
|
| Lab |
van Heesch
|
| Street address |
Heidelberglaan 25
|
| City |
Utrecht |
| ZIP/Postal code |
3584 CS |
| Country |
Netherlands |
| |
|
| Platforms (1) |
|
| Samples (24)
|
|
| This SubSeries is part of SuperSeries: |
| GSE196712 |
5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells |
|
| Relations |
| BioProject |
PRJNA806946 |
Less...
More...