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Translation elongation can control translation initiation on eukaryotic mRNAs

Dominique Chu, Eleanna Kazana, Noémie Bellanger, Tarun Singh, Mick F Tuite, Tobias von der Haar

Author Affiliations

  1. Dominique Chu*,1,,
  2. Eleanna Kazana2,,
  3. Noémie Bellanger2,
  4. Tarun Singh2,
  5. Mick F Tuite2 and
  6. Tobias von der Haar*,2
  1. 1School of Computing, University of Kent, Canterbury, UK
  2. 2Kent Fungal Group School of Biosciences, University of Kent, Canterbury, UK
  1. *Corresponding authors. Tel: +44 1227 823535 (TvdH); +44 1227 827690 (DFC); E‐mails: T.von-der-Haar{at}kent.ac.uk and D.F.Chu{at}kent.ac.uk
  1. These authors contributed equally to this work.

  2. TvdH and DFC designed the study. TVDH, EK, TS and NB conducted experiments. DFC performed computational analyses. TVDH, DFC and MFT analysed data. TVDH, DFC, EK and MFT wrote the paper.

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Abstract

Synonymous codons encode the same amino acid, but differ in other biophysical properties. The evolutionary selection of codons whose properties are optimal for a cell generates the phenomenon of codon bias. Although recent studies have shown strong effects of codon usage changes on protein expression levels and cellular physiology, no translational control mechanism is known that links codon usage to protein expression levels. Here, we demonstrate a novel translational control mechanism that responds to the speed of ribosome movement immediately after the start codon. High initiation rates are only possible if start codons are liberated sufficiently fast, thus accounting for the observation that fast codons are overrepresented in highly expressed proteins. In contrast, slow codons lead to slow liberation of the start codon by initiating ribosomes, thereby interfering with efficient translation initiation. Codon usage thus evolved as a means to optimise translation on individual mRNAs, as well as global optimisation of ribosome availability.

Synopsis

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Codon usage‐dependent ribosomal elongation speed can control translational output by securing fast ribosome clearance of the start codon. Highly expressed proteins preferentially harbour ‘fast codons’ downstream of the initiation site.

  • A novel control mechanism connects codon usage and translation initiation

  • Slow ribosome movement near the start codon interferes with ribosome recruitment

  • Codon usage along the entire ORF can control ribosome movement near the start codon

  • Translational control by codon usage optimises eukaryotic gene expression in vivo

Footnotes

  • The authors declare that they have no conflict of interest.

  • Received May 13, 2013.
  • Revision received October 9, 2013.
  • Accepted October 15, 2013.
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