Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 Apr 2024
05 Apr 2024
Historique:
received:
20
09
2023
accepted:
20
03
2024
medline:
6
4
2024
pubmed:
6
4
2024
entrez:
5
4
2024
Statut:
epublish
Résumé
Nonsense mutations - the underlying cause of approximately 11% of all genetic diseases - prematurely terminate protein synthesis by mutating a sense codon to a premature stop or termination codon (PTC). An emerging therapeutic strategy to suppress nonsense defects is to engineer sense-codon decoding tRNAs to readthrough and restore translation at PTCs. However, the readthrough efficiency of the engineered suppressor tRNAs (sup-tRNAs) largely varies in a tissue- and sequence context-dependent manner and has not yet yielded optimal clinical efficacy for many nonsense mutations. Here, we systematically analyze the suppression efficacy at various pathogenic nonsense mutations. We discover that the translation velocity of the sequence upstream of PTCs modulates the sup-tRNA readthrough efficacy. The PTCs most refractory to suppression are embedded in a sequence context translated with an abrupt reversal of the translation speed leading to ribosomal collisions. Moreover, modeling translation velocity using Ribo-seq data can accurately predict the suppression efficacy at PTCs. These results reveal previously unknown molecular signatures contributing to genotype-phenotype relationships and treatment-response heterogeneity, and provide the framework for the development of personalized tRNA-based gene therapies.
Identifiants
pubmed: 38580646
doi: 10.1038/s41467-024-47258-9
pii: 10.1038/s41467-024-47258-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2957Subventions
Organisme : Cystic Fibrosis Foundation (CF Foundation)
ID : IGNATO2010
Informations de copyright
© 2024. The Author(s).
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