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Translational termination efficiency in mammals is influenced by the base following the stop codon

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McCaughan, K K, Brown, C M, Dalphin, M E, Berry, M J, Tate, W P·1995·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.92.12.5431PMC PMC41708
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Abstract

The base following stop codons in mammalian genes is strongly biased, suggesting that it might be important for the termination event. This proposal has been tested experimentally both in vivo by using the human type I iodothyronine deiodinase mRNA and the recoding event at the internal UGA codon and in vitro by measuring the ability of each of the 12 possible 4-base stop signals to direct the eukaryotic polypeptide release factor to release a model peptide, formylmethionine, from the ribosome. The internal UGA in the deiodinase mRNA is used as a codon for incorporation of selenocysteine into the protein. Changing the base following this UGA codon affected the ratio of termination to selenocysteine incorporation in vivo at this codon: 1:3 (C or U) and 3:1 (A or G). These UGAN sequences have the same order of efficiency of termination as was found with the in vitro termination assay (4th base: A approximately G >> C approximately U). The efficiency of in vitro termination varied in the same manner over a 70-fold range for the UAAN series and over an 8-fold range for the UGAN and UAGN series. There is a correlation between the strength of the signals and how frequently they occur at natural termination sites. Together these data suggest that the base following the stop codon influences translational termination efficiency as part of a larger termination signal in the expression of mammalian genes.

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  • The three stop codons differ substantially in termination efficiency and accuracy in eukaryotes.

    “In fact, multiple lines of evidence suggest much difference in termination efficiency and accuracy among the three stop codons.”

    From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [65]

    The Results report some difference in termination efficiency among the three stop codons, but say it was much less pronounced than the effect of the base following the codon. The paper does not establish substantial differences in termination accuracy among the three codons; its experiments chiefly compare four-base stop signals in mammalian systems. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Similar predictions can be made for +5 or +6 sites, but their effect on translation termination is far less consistent than the +4 site.

    “Similar predictions can also be made with respect to +5 or +6 sites which, however, have their effect far less consistent than the +4 site on translation termination [65].”

    From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [65]

    The Results report that the fifth base has little effect on a strong UGAA termination signal but affects a weak UGAC signal, supporting a context-dependent effect compared with the experimentally established fourth-base effect. The paper notes a statistical bias at the sixth position and cites possible importance in Sindbis virus RNA, but does not establish that sixth-base effects on translation termination are less consistent than fourth-base effects. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In mammalian genes, the effect of the +4 site is consistent among all three stop codons in experimental studies, with termination efficiency of UAAR >> UAAY, UAGR >> UAGY and UGAR >> UGAY both in vitro and in vivo.

    “In mammalian genes, the effect of the +4 site is consistent among all three different stop codons in experimental studies, with termination efficiency of UAAR >> UAAY, UAGR >> UAGY and UGAR >> UGAY both in vitro and in vivo [65].”

    From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [65]

    The abstract and Discussion report that a +4 purine strengthens termination for all three stop codons in vitro. The Results report the corresponding in vivo comparison only for UGA, not for UAA and UAG, so the claim overextends the in vivo finding. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • UAA (especially UAAA) is more efficient than other stop signals.

    “These studies suggest that UAA (especially UAAA) is more efficient than other stop signals.”

    From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [65]

    The Results report high termination activity for UAAA, using it as the reference for comparing the 12 signals. But they also report UGAA ≈ UAAA and say that the fourth base has a much stronger effect than the stop codon itself; they do not establish that UAA signals are generally more efficient than other stop signals. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The translation termination signal is more than a stop codon, including the downstream +4 site (tetranucleotide stop signal).

    “It has long been recognized that the translation termination signal is more than a stop codon [86,87], leading to an early proposal of tetranucleotide stop signal including the downstream +4 site [63,65,87,88].”

    From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [65]

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Cites

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Research works printed but not linked: 8

  1. [5]Martin, R., Phillips-Jones, M. K., Watson, F. J. & Hill, L. S. (1993) Biochem. Soc. Trans. 21, 846–851.
  2. [12]Sharp, P. M., Stenico, M., Peden, J. F. & Lloyd, A. T. (1993) Biochem. Soc. Trans. 21, 835–841.
  3. [16]Sharp, P. M., Burgess, C. J., Cowe, E., Lloyd, A. T. & Mitchell, K. J. (1992) in Transfer RNA in Protein Synthesis, eds. Hatfield, D. L., Lee, B. J. & Pirtle, R. M. (CRC, Boca Raton, FL), pp. 397-425.
  4. [19]Beaudet, A. L. & Caskey, C. T. (1971) Proc. Natl. Acad. Sci. USA
  5. [22]Craigen, W. J., Cook, R. G., Tate, W. P. & Caskey, C. T. (1985) Proc. Natl. Acad. Sci. USA 82, 3616–3620.
  6. [23]Zinoni, F., Birkmann, A., Stadtman, T. C. & Bock, A. (1986) Proc. Natl. Acad. Sci. USA 83, 4650–4654.
  7. [28]Tate, W. P. & Caskey, C. T. (1990) in Ribosomes and Protein Synthesis: A Practical Approach, ed. Spedding, G. (Oxford Univ. Press, Oxford), pp. 81–100.
  8. [36]Yarus, M. & Curran, J. (1992) in Transfer RNA in Protein Synthesis, eds. Hatfield, D. L., Lee, B. J. & Pirtle, R. M. (CRC, Boca Raton, FL), pp. 319–365.

Cited by

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Authors
McCaughan, K. K., Brown, C. M., Dalphin, M. E., Berry, M. J., & Tate, W. P.
Affiliations
  • University of Otago (NZ)
  • Brigham and Women's Hospital (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1995-06-06
Volume
92
Issue
12
Pages
5431-5435
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.92.12.5431
PMC
PMC41708
OpenAlex
W1979098238
Cited by
284
References
1
Citations by year
2026: 9 · 2025: 5 · 2024: 10 · 2023: 8 · 2022: 9 · 2021: 16 · 2020: 14 · 2019: 8 · 2018: 16 · 2017: 9 · 2016: 13 · 2015: 10 · 2014: 5 · 2013: 4 · 2012: 6
FWCI
3.77
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 47320)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
translation termination, stop codon, termination efficiency, selenocysteine incorporation, type I iodothyronine deiodinase, termination signal, mammalian genes, codon usage bias
MeSH terms
Animals, Codon, Humans, Iodide Peroxidase, Mammals, Molecular Sequence Data, Protein Biosynthesis

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