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Nat Commun 2019 Feb 18;101:822. doi: 10.1038/s41467-019-08329-4.
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Engineered transfer RNAs for suppression of premature termination codons.

Lueck JD , Yoon JS , Perales-Puchalt A , Mackey AL , Infield DT , Behlke MA , Pope MR , Weiner DB , Skach WR , McCray PB , Ahern CA .

Premature termination codons (PTCs) are responsible for 10-15% of all inherited disease. PTC suppression during translation offers a promising approach to treat a variety of genetic disorders, yet small molecules that promote PTC read-through have yielded mixed performance in clinical trials. Here we present a high-throughput, cell-based assay to identify anticodon engineered transfer RNAs (ACE-tRNA) which can effectively suppress in-frame PTCs and faithfully encode their cognate amino acid. In total, we identify ACE-tRNA with a high degree of suppression activity targeting the most common human disease-causing nonsense codons. Genome-wide transcriptome ribosome profiling of cells expressing ACE-tRNA at levels which repair PTC indicate that there are limited interactions with translation termination codons. These ACE-tRNAs display high suppression potency in mammalian cells, Xenopus oocytes and mice in vivo, producing PTC repair in multiple genes, including disease causing mutations within cystic fibrosis transmembrane conductance regulator (CFTR).

PubMed ID: 30778053
PMC ID: PMC6379413
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ace cftr mhc1-uaa mt-tr trna

Article Images: [+] show captions
References [+] :
Afgan, The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. 2017, Pubmed