ArticleProceedings of the National Academy of Sciences of the United States of America2021
Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 57 citations in OpenAlex.
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- Comparative evaluation of TRIDs : a strategy to improve treatments.Journal of translational medicine · 2026Article
- TREM2-Mediated Cholesterol Efflux in Macrophages Inhibits Anti-Tumor Immunity via Limitation of CD4Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Common oncogenic mutations in colorectal cancer: drivers of carcinogenesis and potential therapeutic targets.Frontiers in pharmacology · 2026Review
- Near-cognate tRNAs enhance tRNA rejection and prime the ribosome for rapid subsequent tRNA testing.Biophysical journal · 2025Article
- Dystrophin Restorative and Compensatory Gene Addition Therapies for Duchenne Muscular Dystrophy: Could CRISPRa Provide a Realistic Alternative?Muscles (Basel, Switzerland) · 2025Review
- Structural Studies of Nedicistrovirus IRES-Driven, Initiation Factor-independent Translation Shed Light on Key Steps of Eukaryotic Translation Elongation.bioRxiv : the preprint server for biology · 2025Article
- Molecular treatment options for patients carryingMolecular therapy. Nucleic acids · 2025Article
- An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.Nucleic acids research · 2025Article
- Mechanism-based approach in designing patient-specific combination therapies for nonsense mutation diseases.Nucleic acids research · 2025Article
- Mechanism-based approach in designing patient-specific combination therapies for nonsense mutation diseases.bioRxiv : the preprint server for biology · 2024Article
- Promoting readthrough of nonsense mutations in CF mouse model: Biodistribution and efficacy of NV848 in rescuing CFTR protein expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Cystic Fibrosis: A Journey through Time and Hope.International journal of molecular sciences · 2024Review
- Single-Molecule Studies of Cognate and Near-Cognate Elongation in anbioRxiv : the preprint server for biology · 2024Article
- Base editing in humanized dystrophic mice.Molecular therapy. Nucleic acids · 2024Article
- Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.Biomedicines · 2024Review
- Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons.Pharmaceuticals (Basel, Switzerland) · 2024Review
- En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa.JID innovations : skin science from molecules to population health · 2024Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
During protein synthesis, nonsense mutations, resulting in premature stop codons (PSCs), produce truncated, inactive protein products. Such defective gene products give rise to many diseases, including cystic fibrosis, Duchenne muscular dystrophy (DMD), and some cancers. Small molecule nonsense suppressors, known as TRIDs (translational read-through-inducing drugs), stimulate stop codon read-through. The best characterized TRIDs are ataluren, which has been approved by the European Medicines Agency for the treatment of DMD, and G418, a structurally dissimilar aminoglycoside. Previously [1], we applied a highly purified in vitro eukaryotic translation system to demonstrate that both aminoglycosides like G418 and more hydrophobic molecules like ataluren stimulate read-through by direct interaction with the cell's protein synthesis machinery. Our results suggested that they might do so by different mechanisms. Here, we pursue this suggestion through a more-detailed investigation of ataluren and G418 effects on read-through. We find that ataluren stimulation of read-through derives exclusively from its ability to inhibit release factor activity. In contrast, G418 increases functional near-cognate tRNA mispairing with a PSC, resulting from binding to its tight site on the ribosome, with little if any effect on release factor activity. The low toxicity of ataluren suggests that development of new TRIDs exclusively directed toward inhibiting termination should be a priority in combatting PSC diseases. Our results also provide rate measurements of some of the elementary steps during the eukaryotic translation elongation cycle, allowing us to determine how these rates are modified when cognate tRNA is replaced by near-cognate tRNA ± TRIDs.
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