Nonsense Mutations and Suppression

Abstract

A nonsense mutation occurs when a sense codon, one that codes for an amino acid, is changed to one of the chain‐termination codons, 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) such 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, in tRNA, or in translation factors can increase readthrough by altering the initial selection steps, proofreading or quality control in decoding of 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 changes associated with 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.

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: S4, orange; S5, green; S12, red; S17, purple.

close

References

Agarwal D, Gregory ST and O'Connor M (2011) Error‐prone and error‐restrictive mutations affecting ribosomal protein S12. Journal of Molecular Biology 410: 1–9.

Agirrezabala X, Schreiner E, Trabuco LG et al. (2011) Structural insights into cognate versus near‐cognate discrimination during decoding. EMBO Journal 30: 1497–1507.

Benítez‐Páez A, Villarroya M and Armengod ME (2012) The Escherichia coli RlmN methyltransferase is a dual‐specificity enzyme that modifies both rRNA and tRNA and controls translational accuracy. RNA 18: 1783–1795.

Björk GR, Ericson JU, Gustafsson CE et al. (1987) Transfer RNA modification. Annual Review of Biochemistry 56: 263–287.

Brenner S and Stretton AOW (1965) Phase shifting of amber and ochre mutants. Journal of Molecular Biology 13: 944–946.

Celis JE and Piper PW (1982) Compilation of mutant suppressor tRNA sequences. Nucleic Acids Research 10: r83–r91.

Chang Z, Inokuchi H and Ozeki H (1990) Novel UGA‐suppressors in Escherichia coli K‐12. Japanese Journal of Genetics 65: 71–81.

Cridge AG, Major LL, Mahagaonkar AA et al. (2006) Comparison of characteristics and function of translation termination signals between and within prokaryotic and eukaryotic organisms. Nucleic Acids Research 34: 1959–1973.

Demeshkina N, Jenner L, Westhof E, Yusupov M and Yusupova G (2012) A new understanding of the decoding principle on the ribosome. Nature 484: 256–259.

Dingermann T, Reindl N, Brechner T, Werner H and Nerke K (1990) Nonsense suppression in Dictyostelium discoideum. Developmental Genetics 11: 410–417.

Eggertsson G and Söll D (1988) Transfer ribonucleic acid‐mediated suppression of termination codons in Escherichia coli. Microbiological Reviews 52: 354–374.

Gatti RA (2012) SMRT compounds correct nonsense mutations in primary immunodeficiency and other genetic models. Annals of the New York Academy of Sciences 1250: 33–40.

Hartman PE and Roth JR (1973) Mechanisms of suppression. Advances in Genetics 17: 1–105.

Hodgkin J (2005) Genetic suppression. In: WormBook (ed.) The C. elegans Research Community. pp 1–13. WormBook, doi/10.1895/wormbook.1.7.1, http://www.wormbook.org.

Hudziak RM, Laski FA, RajBhandary UL, Sharp PA and Capecchi MR (1982) Establishment of mammalian cell lines containing multiple nonsense mutations and functional suppressor tRNA genes. Cell 31: 137–146.

Hughes D, Atkins JF and Thompson S (1987) Mutants of elongation factor Tu promote ribosomal frameshifting and nonsense readthrough. EMBO Journal 6: 4235–4239.

Inge‐Vechtomov S, Zhouravleva G and Philippe M (2003) Eukaryotic release factors (eRFs) history. Biology of the Cell 95: 195–209.

Johansson M, Zhang J and Ehrenberg M (2012) Genetic code translation displays a linear trade‐off between efficiency and accuracy of tRNA selection. Proceedings of the National Academy of Sciences of the USA 109: 131–136.

Kawakami K, Inada T and Nakamura Y (1988) Conditionally lethal and recessive UGA‐suppressor mutations in the prfB gene encoding peptide chain release factor 2 of Escherichia coli. Journal of Bacteriology 170: 5378–5381.

Keeling KM and Bedwell DM (2011) Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases. Wiley Interdisciplinary Reviews: RNA 2: 837–852.

Kohli J, Kwong T, Altruda F, Söll D and Wahl G (1979) Characterization of a UGA‐suppressing serine tRNA from Schizosaccharomyces pombe with the help of a new in vitro assay system for eukaryotic suppressor tRNAs. Journal of Biological Chemistry 254: 1546–1551.

McClory SP, Devaraj A, Qin D, Leisring JM and Fredrick K (2011) Chap. 19 Mutations in 16S rRNA that decrease the fidelity of translation. In: Rodnina MV, Wintermeyer W and Green R (eds) Ribosomes: Structure, Function and Dynamics, pp 237–247. Wien: Springer‐Verlag.

Merritt GH, Naemi WR, Mugnier P et al. (2010) Decoding accuracy in eRF1 mutants and its correlation with pleiotropic quantitative traits in yeast. Nucleic Acids Research 38: 5479–5492.

Michaels ML, Kim CW, Matthews DA and Miller JH (1990) Escherichia coli thymidylate synthase: amino acid substitutions by suppression of amber nonsense mutations. Proceedings of the National Academy of Sciences of the USA 87: 3957–3961.

Mikuni O, Ito K, Moffat J et al. (1994) Identification of the prfC gene, which encodes peptide‐chain‐release factor 3 of Escherichia coli. Proceedings of the National Academy of Sciences of the USA 91: 5798–5802.

Miller JH (1991) Use of nonsense suppression to generate altered proteins. Methods in Enzymology 208: 543–563.

Nie L, Lavinder JJ, Sarkar M, Stephany K and Magliery TJ (2011) Synthetic approach to stop‐codon scanning mutagenesis. Journal of the American Chemical Society 133: 6177–6186.

O'Connor M (2009) Helix 69 in 23S rRNA modulates decoding by wild type and suppressor tRNAs. Molecular Genetics and Genomics 282: 371–380.

Pérez B, Rodriguez‐Pombo P, Ugarte M and Desviat LR (2012) Readthrough strategies for therapeutic suppression of nonsense mutations in inherited metabolic disease. Molecular Syndromology 3: 230–236.

Rydén M, Murphy J, Martin R, Isaksson L and Gallant J (1986) Mapping and complementation studies of the gene for release factor 1. Journal of Bacteriology 168: 1066–1069.

Rydén SM and Isaksson LA (1984) A temperature‐sensitive mutant of Escherichia coli that shows enhanced misreading of UAG/A and increased efficiency for some tRNA nonsense suppressors. Molecular Genetics and Genomics 193: 38–45.

Schmeing TM, Voorhees RM, Kelley AC and Ramakrishnan V (2011) How mutations in tRNA distant from the anticodon affect the fidelity of decoding. Nature Structural & Molecular Biology 18: 432–436.

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.

Singaravelan B, Roshini BR and Munavar MH (2010) Evidence that the supE44 mutation of Escherichia coli is an amber suppressor allele of glnX and that it also suppresses ochre and opal nonsense mutations. Journal of Bacteriology 192: 6039–6044.

Stalder L and Mühlemann O (2008) The meaning of nonsense. Trends in Cell Biology 18: 315–321.

Stansfield I, Jones KM, Herbert P et al. (1998) Missense translation errors in Saccharomyces cerevisiae. Journal of Molecular Biology 282: 13–24.

Sun Q, Vila‐Sanjurjo A and O'Connor M (2011) Mutations in the intersubunit bridge regions of 16S rRNA affect decoding and subunit‐subunit interactions on the 70S ribosome. Nucleic Acids Research 39: 3321–3330.

Thompson J, Kim DF, O'Connor M et al. (2001) Analysis of mutations at residues A2451 and G2447 of 23S rRNA in the peptidyltransferase active site of the 50S ribosomal subunit. Proceedings of the National Academy of Sciences of the USA 98: 9002–9007.

Tran DK, Finley J, Vila‐Sanjurjo A et al. (2011) Tertiary interactions between helices h13 and h44 in 16S RNA contribute to the fidelity of translation. FEBS Journal 278: 4405–4412.

Vijgenboom E, Vink T, Kraal B and Bosch L (1985) Mutants of the elongation factor EF‐Tu, a new class of nonsense suppressors. EMBO Journal 4: 1049–1052.

Wickner RB, Edskes HK, Roberts BT et al. (2004) Prions: proteins as genes and infectious entities. Genes & Development 18: 470–485.

Wimberly BT, Brodersen DE, Clemons WM Jr et al. (2000) Structure of the 30S ribosomal subunit. Nature 407: 327–339.

Yusupov MM, Yusupova GZ, Baucom A et al. (2001) Crystal structure of the ribosome at 5.5A resolution. Science 292: 883–896.

Zaher HS and Green R (2009) Quality control by the ribosome following peptide bond formation. Nature 457: 161–166.

Zaher HS and Green R (2010) Hyperaccurate and error‐prone ribosomes exploit distinct mechanisms during tRNA selection. Molecular Cell 39: 110–120.

Zaher HS and Green R (2011) A primary role for release factor 3 in quality control during translation elongation in Escherichia coli. Cell 147: 396–408.

Further Reading

Engelberg‐Kulka H and Schoulaker‐Schwarz R (1996) Suppression of termination codons. In: Neidhardt FC (ed.) Escherichia coli and Salmonella: Cellular and Molecular Biology, pp 909–924. Washington DC: ASM Press.

Gorini L (1970) Informational suppression. Annual Review of Genetics 4: 107–134.

Kurland CG, Hughes D and Ehrenberg M (1996) Limitations of translational accuracy. In: Neidhardt FC (ed.) Escherichia coli and Salmonella: Cellular and Molecular Biology, pp 979–1004. Washington DC: ASM Press.

Murgola EJ (1994) Translational suppression: when two wrongs DO make a right. In: Söll D and RajBhandary UL (eds) tRNA: Structure, Biosynthesis and Function, pp 491–510. Washington DC: ASM Press.

Ogle JM and Ramakrishnan V (2005) Structural insights into translational fidelity. Annual Review of Biochemistry 74: 129–177.

Parker J (1989) Errors and alternatives in reading the universal genetic code. Microbiological Reviews 53: 273–298.

Rodnina MV, Wintermeyer W and Green R (eds) (2011) Ribosomes: Structure, Function and Dynamics. Wien: Springer‐Verlag.

Yadavalli SS and Ibba M (2012) Quality control in aminoacyl‐tRNA synthesis its role in translational fidelity. Advances in Protein Chemistry and Structural Biology 86: 1–43.

Zaher HS and Green R (2009) Fidelity at the molecular level: lessons from protein synthesis. Cell 136: 746–762.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Herrington, Muriel B(Oct 2013) Nonsense Mutations and Suppression. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000824.pub2]