Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

The drug ataluren restores activity to otherwise nonfunctional nonsense alleles, a capability possibly reflecting the insertion of near-cognate aminoacyl tRNAs at premature termination codons during protein synthesis. Because nonsense alleles comprise a significant fraction of all alleles causing inherited disorders, drugs that promote such nonsense codon readthrough have broad therapeutic potential. However, the effectiveness of therapeutic nonsense suppression depends on the nature of the amino acids inserted at each of the three nonsense codons. Here we demonstrate that ataluren does indeed promote insertion of near-cognate tRNAs at nonsense codons, that the latter process yields functional proteins, and that specific codon:anticodon base pairings are critical to this process. These results should enable predictions of better clinical outcomes with therapeutic nonsense suppression.