Open AccessAtaluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms
Author(s) -
Martin Y Ng,
Hong Li,
Mikel Ghelfi,
Yale E. Goldman,
Barry S. Cooperman
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2020599118
Subject(s) - context (archaeology) , nonsense , nonsense mutation , translation (biology) , aminoglycoside , biology , chemistry , computational biology , medicine , genetics , mutation , antibiotics , messenger rna , gene , missense mutation , paleontology
Significance Nonsense mutations giving rise to premature stop codons (PSCs) cause many diseases, creating the need to develop safe and effective translational read-through–inducing drugs (TRIDs). The current best-characterized TRIDs are ataluren and aminoglycosides. Only ataluren has been approved for clinical use, albeit in a limited context. Here, we provide rate measurements of elementary steps in a single eukaryotic translation elongation cycle, allowing us to demonstrate that ataluren and the aminoglycoside G418 employ orthogonal mechanisms in stimulating PSC read-through: ataluren by inhibiting release factor-dependent termination of protein synthesis and G418 by increasing functional near-cognate transfer RNA mispairing, which permits continuation of synthesis. We conclude that development of new TRIDs combatting PSC diseases should prioritize those directed toward inhibiting termination.