Review
Sense from nonsense: therapies for premature stop codon diseases

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Ten percent of inherited diseases are caused by premature termination codon (PTC) mutations that lead to degradation of the mRNA template and to the production of a non-functional, truncated polypeptide. In addition, many acquired mutations in cancer introduce similar PTCs. In 1999, proof-of-concept for treating these disorders was obtained in a mouse model of muscular dystrophy, when administration of aminoglycosides restored protein translation by inducing the ribosome to bypass a PTC. Since, many studies have validated this approach, but despite the promise of PTC readthrough therapies, the mechanisms of translation termination remain to be precisely elucidated before even more progress can be made. Here, we review the molecular basis for PTC readthrough in eukaryotes and describe currently available compounds with significant therapeutic potential for treating genetic disorders and cancer.

Section snippets

Translation termination and premature termination codons (PTCs)

In organisms that use the standard genetic code, including humans, translation termination occurs when one of the three stop codons – UAA, UGA, or UAG – enters the ribosomal A site. Extra-ribosomal proteins known as class I release factors recognize all three termination codons. Translation termination is not 100% efficient, and its efficiency depends on competition between stop codon recognition by a class I release factor and decoding of the stop codon by a near-cognate tRNA (paired using two

Mechanisms of translation termination

In eukaryotes, two release factors mediate translation termination, eRF1 and the GTPase eRF3. Full or partial X-ray structures are available for both proteins, providing insight into their function, as does recently obtained nuclear magnetic resonance (NMR) data that has made it possible to complete the structure of the C-terminal domain of eRF1 (Figure 2a) 18, 19, 20. The shape of human eRF1 resembles a tRNA, with functional motifs targeting both the peptidyl transferase center and the

The aminoglycoside family

Aminoglycosides are widely used drugs that inhibit bacterial ribosome function by binding to specific ribosomal subunits. Aminoglycosides are oligosaccharides with either streptidine (e.g., streptomycin) or 2-deoxystreptidine (e.g., gentamicin, amikacin, tobramycin) as the molecular nucleus and variable numbers of sugar rings and ammonium groups (Figure 4a) [41]. The antibacterial action of aminoglycosides involves targeting the 16S rRNA subunit of the 30S bacterial ribosome, resulting in the

PTC and mRNA stability

The primary prerequisite for a therapeutic benefit of PTC suppression is the presence of a nonsense mutation-containing, translatable mRNA that is not efficiently degraded by nonsense-mediated mRNA decay (NMD). NMD is a quality control pathway for the degradation of PTC-containing mRNA that is thought to occur in most, if not all, eukaryotes (for reviews see 67, 68; Box 1). This quality control system prevents deleterious dominant negative effects that may be exerted by C-terminally truncated

Therapeutic approaches

The therapeutic potential of suppressing translation termination using pharmacological agents has now been demonstrated beyond a reasonable doubt, mainly in animal models such as the mdx mouse, which provided the first in vivo proof-of-concept for this approach [5]. PTC suppression has also been evaluated in many preclinical model systems of diverse human genetic disorders, including ataxia–telangiectasia (ATM), Hailey–Hailey disease, Hurler syndrome (α-l-iduronidase deficiency), spinal

Future perspectives

There is a strong and intricate relationship between PTC-bearing mRNA availability and translational readthrough. Indeed, the presence of a premature stop codon within the reading frame of genes elicits NMD, thereby reducing the mRNA pool available for translation. This may account, in part, for the limited efficiency of readthrough suppressors, even if some studies show that readthrough can partially counteract NMD. Interestingly, NMD inhibition by siRNA directed against UPF1 or UPF2, key

Acknowledgment

We would like to thank Célia Floquet for her interesting comments on this manuscript. We also thank Marc Capet for the representation of the drugs using MM2 with Chem3D Ultra 7.0. English usage was corrected by Alex Edelman & Associates. This work is supported by the Association pour la Recherche sur le Cancer (ARC; grant No. SFI20101201647), ANR (grant ANR-2011-BSV6-011-01), the Ligue Nationale Contre le Cancer (LNCC; grant 2FI10650MIRO), the Association Française contre les Myopathies (AFM;

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