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Review
. 2014:15:371-94.
doi: 10.1146/annurev-genom-091212-153527. Epub 2014 Apr 18.

Therapeutics based on stop codon readthrough

Kim M Keeling  1 , Xiaojiao Xue, Gwen Gunn, David M Bedwell
Affiliations
Review

Therapeutics based on stop codon readthrough

Kim M Keeling et al. Annu Rev Genomics Hum Genet. 2014.

Abstract

Nonsense suppression therapy encompasses approaches aimed at suppressing translation termination at in-frame premature termination codons (PTCs, also known as nonsense mutations) to restore deficient protein function. In this review, we examine the current status of PTC suppression as a therapy for genetic diseases caused by nonsense mutations. We discuss what is currently known about the mechanism of PTC suppression as well as therapeutic approaches under development to suppress PTCs. The approaches considered include readthrough drugs, suppressor tRNAs, PTC pseudouridylation, and inhibition of nonsense-mediated mRNA decay. We also discuss the barriers that currently limit the clinical application of nonsense suppression therapy and suggest how some of these difficulties may be overcome. Finally, we consider how PTC suppression may play a role in the clinical treatment of genetic diseases caused by nonsense mutations.

Keywords: nonsense mutation; nonsense suppression therapy; premature termination codons; readthrough.

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Figures

Figure 1
Figure 1
Steps in aminoacyl-tRNA discrimination during eukaryotic translation elongation: (a) initial selection and (b) proofreading.
Figure 2
Figure 2
Mechanism of eukaryotic translation termination.
Figure 3
Figure 3
(a) Normal and (b) premature termination codons. The messenger ribonucleoprotein (mRNP) structure leads to a higher basal level of termination suppression (readthrough) at the latter compared with the former.
Figure 4
Figure 4
Nonsense-mediated mRNA decay (NMD) reduces premature termination codon (PTC) suppression efficiency. (a) Translation termination at a PTC induces mRNA degradation by NMD. (b) NMD inhibition enhances the amount of protein restored by PTC suppression.
See this image and copyright information in PMC

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