ArticlePLoS genetics2012
Statistical analysis of readthrough levels for nonsense mutations in mammalian cells reveals a major determinant of response to gentamicin.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 156 citations in OpenAlex.
- Gentamicin Induces Laminin 332 and Improves Wound Healing in Junctional Epidermolysis Bullosa Patients with Nonsense Mutations.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Trial
- Release factor 3 degradation enhances aminoglycoside-mediated translational readthrough at MECP2 nonsense mutations.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Comparative evaluation of TRIDs : a strategy to improve treatments.Journal of translational medicine · 2026Article
- A Translational Roadmap for Neurological Nonsense Mutation Disorders.International journal of molecular sciences · 2026Review
- Identity, functional consequences, and context effects of amino acids inserted during suppression of CFTR nonsense mutations.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2026Article
- Genomic stop codon scanning reveals quantitative principles of nonsense-mediated mRNA decay.bioRxiv : the preprint server for biology · 2025Article
- Defining the high-translational readthrough stop codon context.PLoS genetics · 2025Article
- Massive mutagenesis reveals an incomplete amyloid motif in Bri2 that turns amyloidogenic upon C-terminal extension.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Ribosomal A-site interactions with near-cognate tRNAs drive stop codon readthrough.Nature structural & molecular biology · 2025Article
- A W1282X cystic fibrosis mouse allows the study of pharmacological and gene-editing therapeutics to restore CFTR function.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2025Article
- An In Vitro RNA Editing-Based Reporter Assay for Transcriptional Activity of Therapeutic Gene in Gene Therapy Products.Molecules (Basel, Switzerland) · 2024Article
- StopKB: a comprehensive knowledgebase for nonsense suppression therapies.Database : the journal of biological databases and curation · 2024Article
- Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules.Nature genetics · 2024Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.Biomedicines · 2024Review
- Eukaryotic release factor 1 from Euplotes promotes frameshifting at premature stop codons in human cells.iScience · 2024Article
- A system of reporters for comparative investigation of EJC-independent and EJC-enhanced nonsense-mediated mRNA decay.Nucleic acids research · 2024Article
- Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations.Nature communications · 2024Article
- Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease.Cell stem cell · 2024Article
- Extended stop codon context predicts nonsense codon readthrough efficiency in human cells.Nature communications · 2024Article
30 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The efficiency of translation termination depends on the nature of the stop codon and the surrounding nucleotides. Some molecules, such as aminoglycoside antibiotics (gentamicin), decrease termination efficiency and are currently being evaluated for diseases caused by premature termination codons. However, the readthrough response to treatment is highly variable and little is known about the rules governing readthrough level and response to aminoglycosides. In this study, we carried out in-depth statistical analysis on a very large set of nonsense mutations to decipher the elements of nucleotide context responsible for modulating readthrough levels and gentamicin response. We quantified readthrough for 66 sequences containing a stop codon, in the presence and absence of gentamicin, in cultured mammalian cells. We demonstrated that the efficiency of readthrough after treatment is determined by the complex interplay between the stop codon and a larger sequence context. There was a strong positive correlation between basal and induced readthrough levels, and a weak negative correlation between basal readthrough level and gentamicin response (i.e. the factor of increase from basal to induced readthrough levels). The identity of the stop codon did not affect the response to gentamicin treatment. In agreement with a previous report, we confirm that the presence of a cytosine in +4 position promotes higher basal and gentamicin-induced readthrough than other nucleotides. We highlight for the first time that the presence of a uracil residue immediately upstream from the stop codon is a major determinant of the response to gentamicin. Moreover, this effect was mediated by the nucleotide itself, rather than by the amino-acid or tRNA corresponding to the -1 codon. Finally, we point out that a uracil at this position associated with a cytosine at +4 results in an optimal gentamicin-induced readthrough, which is the therapeutically relevant variable.
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