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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.

Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms