Trends in Molecular Medicine
ReviewSense from nonsense: therapies for premature stop codon diseases
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;
References (92)
- et al.
Introducing sense into nonsense in treatments of human genetic diseases
Trends Genet.
(2008) Poly-L-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model
J. Biol. Chem.
(2009)Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations
Bioorg. Med. Chem.
(2010)Crystal structure and functional analysis of the eukaryotic class II release factor eRF3 from S. pombe
Mol. Cell
(2004)The crystal structure of human eukaryotic release factor eRF1–mechanism of stop codon recognition and peptidyl-tRNA hydrolysis
Cell
(2000)Distinct eRF3 requirements suggest alternate eRF1 conformations mediate peptide release during eukaryotic translation termination
Mol. Cell
(2008)In vitro reconstitution of eukaryotic translation reveals cooperativity between release factors eRF1 and eRF3
Cell
(2006)Kinetic analysis of interaction of eukaryotic release factor 3 with guanine nucleotides
J. Biol. Chem.
(2006)Crystal structures of the ribosome in complex with release factors RF1 and RF2 bound to a cognate stop codon
Cell
(2005)- et al.
A model for how ribosomal release factors induce peptidyl-tRNA cleavage in termination of protein synthesis
Mol. Cell
(2007)