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Roadblocks and resolutions in eukaryotic translation

  • Review Article
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From Nature Reviews Molecular Cell Biology

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Abstract

During protein synthesis, ribosomes encounter many roadblocks, the outcomes of which are largely determined by substrate availability, amino acid features and reaction kinetics. Prolonged ribosome stalling is likely to be resolved by ribosome rescue or quality control pathways, whereas shorter stalling is likely to be resolved by ongoing productive translation. How ribosome function is affected by such hindrances can therefore have a profound impact on the translational output (yield) of a particular mRNA. In this Review, we focus on these roadblocks and the resumption of normal translation elongation rather than on alternative fates wherein the stalled ribosome triggers degradation of the mRNA and the incomplete protein product. We discuss the fundamental stages of the translation process in eukaryotes, from elongation through ribosome recycling, with particular attention to recent discoveries of the complexity of the genetic code and regulatory elements that control gene expression, including ribosome stalling during elongation, the role of mRNA context in translation termination and mechanisms of ribosome rescue that resemble recycling.

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Fig. 1: Overview of eukaryotic translation.
Fig. 2: Translation elongation and resolution of ribosome stalling.
Fig. 3: Translation termination and the role of mRNP context.
Fig. 4: Ribosome recycling and rescue.

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Anthony P. Schuller & Rachel Green

  2. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Rachel Green

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A.P.S. and R.G. researched data for the article, made substantial contributions to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Rachel Green.

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Glossary

P site

Peptidyl site of the ribosome, which binds the tRNA attached to the elongating peptide chain.

Aminoacyl-tRNAs

tRNA molecules charged with their corresponding amino acids.

E site

Exit site of the ribosome, which binds the deacylated (uncharged) tRNA after translocation and before this tRNA dissociates from the ribosome.

A site

Aminoacyl site of the ribosome, which binds the incoming aminoacyl-tRNA for peptide-bond formation.

Peptidyl-tRNA

tRNA molecule covalently attached to the nascent polypeptide.

Ribosome rescue

Mechanism of ribosomal subunit dissociation when translation stalling cannot be resolved.

Hypusine

A unique lysine post-translational modification of eIF5A that is crucial for its translation elongation and termination functions.

Peptidyl-transferase centre

The active site of the ribosome where peptide-bond formation and peptide release occur during translation.

Ribosome profiling

High-throughput sequencing method that provides a global snapshot of translating ribosomes in the cell by mapping mRNA fragments protected by ribosomes.

5PSeq

Technique to identify mRNAs that contain phosphorylated 5′ ends resulting from exonucleolytic (5′ to 3′) mRNA degradation pathways.

Förster resonance energy transfer

(FRET). Biophysical technique to monitor molecular dynamics that relies on energy transfer between two fluorescent molecules located close in space.

Aminoacylation

Chemical reaction whereby a tRNA molecule is ‘charged’ with its corresponding amino acid.

Near-cognate tRNA

tRNA molecule that is not a perfect match to the codon; usually unmatched at one position of the codon.

Wobble decoding

Codon–anticodon interactions typically at the third (3′) position of the codon that do not follow strict Watson–Crick base pairing rules.

Unfolded protein response

Cellular stress response that is activated upon the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum.

Ribosomopathies

Broad group of human disorders resulting from ribosomal protein haploinsufficiency or defects in ribosome biogenesis.

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Schuller, A.P., Green, R. Roadblocks and resolutions in eukaryotic translation. Nat Rev Mol Cell Biol 19, 526–541 (2018). https://doi.org/10.1038/s41580-018-0011-4

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