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Control of translation elongation in health and disease

Knight, John R.P., Garland, Gavin, Pöyry, Tuija, Mead, Emma, Vlahov, Nikola, Sfakianos, Aristeidis, Grosso, Stefano, De-Lima-Hedayioglu, Fabio, Mallucci, Giovanna R., von der Haar, Tobias, and others. (2020) Control of translation elongation in health and disease. Disease Models & Mechanisms, 13 (3). ISSN 1754-8403. E-ISSN 1754-8411. (doi:10.1242/dmm.043208) (KAR id:80923)

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Abstract

Regulation of protein synthesis makes a major contribution to post-transcriptional control pathways. During disease, or under stress, cells initiate processes to reprogramme protein synthesis and thus orchestrate the appropriate cellular response. Recent data show that the elongation stage of protein synthesis is a key regulatory node for translational control in health and disease. There is a complex set of factors that individually affect the overall rate of elongation and, for the most part, these influence either transfer RNA (tRNA)- and eukaryotic elongation factor 1A (eEF1A)-dependent codon decoding, and/or elongation factor 2 (eEF2)-dependent ribosome translocation along the mRNA. Decoding speeds depend on the relative abundance of each tRNA, the cognate:near-cognate tRNA ratios and the degree of tRNA modification, whereas eEF2-dependent ribosome translocation is negatively regulated by phosphorylation on threonine-56 by eEF2 kinase. Additional factors that contribute to the control of the elongation rate include epigenetic modification of the mRNA, coding sequence variation and the expression of eIF5A, which stimulates peptide bond formation between proline residues. Importantly, dysregulation of elongation control is central to disease mechanisms in both tumorigenesis and neurodegeneration, making the individual key steps in this process attractive therapeutic targets. Here, we discuss the relative contribution of individual components of the translational apparatus (e.g. tRNAs, elongation factors and their modifiers) to the overall control of translation elongation and how their dysregulation contributes towards disease processes.

Item Type: Article
DOI/Identification number: 10.1242/dmm.043208
Uncontrolled keywords: cancer; neurodegenerative disorders
Subjects: R Medicine
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Susan Davies
Date Deposited: 20 Apr 2020 11:24 UTC
Last Modified: 21 Apr 2020 08:33 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/80923 (The current URI for this page, for reference purposes)
von der Haar, Tobias: https://orcid.org/0000-0002-6031-9254
Smales, C. Mark: https://orcid.org/0000-0002-2762-4724
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