Allan Jacobson

Bijoyita Roy

Briana Johnson

Christopher R. Trotta

David M. Bedwell

Ellen M. Welch

James A. Mobley

Jin Zhuo

John D. Leszyk

Jumana Dakka

Kim M. Keeling

Steven M. Rowe

Venkateshwar Mutyam

Westhof

Westley J. Friesen

Xiaojiao Xue

Yuki Tomizawa

Significance
          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.</jats:p

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Proceedings of the National Academy of Sciences

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

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

Abstract

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