ArticleNucleic acids research2025
High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs.
Article in Nucleic acids research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.Molecular therapy. Nucleic acids · 2026Article
- RiboScreenBiomedicines · 2026Review
- Tetrahedral DNA nanostructure-delivered suppressor tRNA ameliorates nephropathy inNAR molecular medicine · 2026Article
- Mistranslation from an endogenous tRNA variant in human pan-genome cell lines.Nucleic acids research · 2026Article
- Anticodon-edited transfer RNAs (ACE-tRNAs) encoded as therapeutic nonviral minimal DNA vectors.Nucleic acids research · 2026Article
- Mistranslating tRNA variants impact the proteome and phosphoproteome of Saccharomyces cerevisiae.G3 (Bethesda, Md.) · 2026Article
- Mistranslating tRNA variants impact the proteome and phosphoproteome ofbioRxiv : the preprint server for biology · 2025Article
- Anticodon Edited Transfer RNAs (ACE-tRNAs) Encoded as Therapeutic Nonviral Minimal DNA Vectors.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
7 authors.
Funding
Abstract
Nonsense mutations generate premature termination codons (PTCs) that are responsible for 11% of genetic disease alleles. The arginine (Arg, CGA) to stop (UGA) mutation is the most common PTC. Humans encode >600 transfer RNA (tRNA) genes with many identical and similar copies. We developed a dual fluorescent reporter to quantify PTC readthrough in live cells and found single nucleotide mutations of human tRNAArg gene variants enabled differential nonsense suppression that depended on the tRNA sequence and the cell type. We investigated G36A variants of all six human tRNAArgUCG isodecoders, and only the TCG-6-1 tRNA, where G36A occurs in 0.01% of human genomes, was unable to translate nonsense codons. With tRNA sequencing, we showed that a suppressor tRNA derived from the TCG-3-1 gene was expressed 2.1-fold higher and generated 1.8-fold more nonsense suppression than a tRNA derived from the TCG-4-1 gene. In a neuroblastoma model of frontotemporal dementia, we observed >70% readthrough of progranulin R493X with a suppressor tRNA that represented 5%-18% of the total tRNAArg pool. The tRNAs outperformed aminoglycoside-induced nonsense suppression in efficacy, tolerability to the cells, and translation fidelity according to mass spectrometry. Our studies show that human nonsense suppressor tRNAs can correct genetic defects that cause disease.
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