Translational Readthrough of Premature Termination Codons in a Therapeutic Context

Abstract

Coding sequences are defined between a start and a stop codon. The appearance of a nonsense mutation in a coding sequence creates a premature termination codon (PTC), preventing the correct production of the corresponding protein by interrupting translation and inducing the degradation of the transcript via the nonsense‐mediated mRNA decay (NMD) pathway. Over the past 10 years, there has been considerable interest in the possibility of suppressing in‐frame PTCs for therapeutic purposes. Indeed, some drugs have been shown to promote PTC readthrough by binding to mammalian ribosomes, thereby partially restoring the synthesis of a full‐length protein in cultured mammalian cells and animal models. This translational suppression strategy represents a promising therapeutic approach for genetic diseases and cancers due to a PTC.

Key Concepts

  • The stop codons in humans are UAA, UAG and UGA, and they are recognised by release factors.
  • Near‐cognate tRNA‐binding codons display base pairing for only two of the three bases of the codon.
  • Stop codon readthrough is the process by which the ribosome incorporates a near‐cognate tRNA at the stop codon.

Keywords: stop codon readthrough; ribosome; translation; premature termination codon; genetic diseases

Figure 1. Therapeutic strategy. Readthrough compounds compromise translation termination at PTC, allowing the synthesis of a full‐length protein. The re‐expression of the (hopefully active) full‐length protein counteracts the defects caused by the defective allele.
Figure 2. Schematic diagram of the sites of action of known readthrough inducers. The ribosomal structure used is the yeast 80S ribosome (PBD 4V88). The rRNA is shown in grey, and the ribosomal proteins from the 40S and 60S subunits are shown in orange and yellow, respectively. The upper panel shows a higher magnification for the visualisation of negamycin binding to helix 34 in the ribosome (PDB 4W2I); the lower panel shows a higher magnification for the visualisation of G418 binding to helix 44 in the yeast ribosome (PDB 4U40). For the sake of simplicity, the mRNA and tRNA are not shown.
Figure 3. Distribution of the amino acids inserted at the stop codon during readthrough in yeast. Three amino acids are found at each stop codon.
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Further Reading

Bidou L and Allamand V (2010) Nonsense mutations causing inherited diseases: therapeutic approaches. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0022433.

Bordeira‐Carrico R, Pego AP, Santos M and Oliveira C (2012) Cancer syndromes and therapy by stop‐codon readthrough. Trends in Molecular Medicine 18: 667–678.

Keeling KM, Xue X, Gunn G and Bedwell DM (2014) Therapeutics based on stop codon readthrough. Annual Review of Genomics and Human Genetics 15: 371–394.

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How to Cite close
Bidou, Laure, Sandra, Blanchet, and Olivier, Namy(Feb 2016) Translational Readthrough of Premature Termination Codons in a Therapeutic Context. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024623]