Nonsense Mutations and Suppression

Abstract

A nonsense mutation occurs when a sense codon, one that codes for an amino acid, is changed to a chain‐termination codon, UAG, UAA or UGA. A nonsense suppressor can result from a second mutation affecting the translational apparatus. This mutation enables the cell to insert an amino acid in response to the nonsense codon, resulting in a wild‐type or near wild‐type phenotype. Some suppressor mutations change the anticodon of a transfer ribonucleic acid (tRNA) so that it can pair with the nonsense codon. Other suppressors increase the readthrough of the nonsense mutation. Readthrough occurs at low levels but changes in the ribosome, tRNA or in translation factors can increase readthrough by altering the initial selection steps, proofreading or quality control in decoding the messenger RNA. Manipulation of the accuracy of translation holds promise as a method for the treatment of genetic diseases, many of which result from nonsense mutations.

Key Concepts

  • Suppression results when one mutation counteracts the effect of another mutation to give a wild‐type phenotype.
  • The nonsense codons UAG, UAA and UGA do not code for amino acids, but signal the end of the protein‐coding sequence in the mRNA.
  • Nonsense suppression competes with chain termination.
  • Errors occur during translation and include reading a nonsense codon as sense as well as misreading and frameshifting.
  • Decoding during elongation involves conformational changes in the ribosome, tRNA and EF‐Tu.
  • Changes in the ribosome or other components of the translational apparatus can modify decoding and thus enhance or reduce readthrough of nonsense codons.

Keywords: tRNA; suppression; translation; ribosome; decoding; nonsense suppressors; readthrough of nonsense codons

Figure 1. tRNA. Yeast tRNAPhe (PDB ID 1EHZ, Shi and Moore, ) is shown in spacefill with the anticodon in red, the remainder of the anticodon stem–loop in light blue, the D stem–loop in magenta with residue G24 in light magenta, the T stem–loop in light orange, the variable loop in grey, the acceptor stem in cyan and the ACCA 3′ acceptor end in yellow. The amino acid attaches to the 3′ A. All tRNAs have a similar three‐dimensional structure. Reprinted from Shi H and Moore PB (2000) The crystal structure of yeast phenylalanine tRNA at 1.93A resolution: a classic structure revisited. RNA 6: 1091–1105.
Figure 2. An elongation step in protein synthesis. A noncognate tRNA is unlikely to bind when it enters the decoding centre. Near cognate tRNA may bind especially if the two 3′ nucleotides of the anticodon can base pair with the 5′ nucleotides of the codon. Near cognate tRNAs that bind can be rejected during the initial selection or during proofreading. After peptide bond formation and translocation, a P‐site mismatch may trigger the quality control activity.
Figure 3. 30S ribosomal subunit. The Thermus thermophilus 30S ribosomal subunit (PDB ID 1J5E, Wimberly et al., ) is shown. The view is of the side that contacts the 50S subunit. The 16S ribosomal RNA is shown as a backbone trace in light blue with helix 44 in dark blue. Most proteins are shown as cartoons in cyan. The proteins involved in accuracy are shown in spacefill and are coloured as follows: uS4, orange; uS5, green; uS12 and red; uS17, purple.
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Herrington, Muriel B(Feb 2018) Nonsense Mutations and Suppression. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000824.pub3]