Controlling translation elongation efficiency: tRNA regulation of ribosome flux on the mRNA

Abstract

Gene expression can be regulated by a wide variety of mechanisms. One example concerns the growing body of evidence that the protein-production rate can be regulated at the level of translation elongation by controlling ribosome flux across the mRNA. Variations in the abundance of tRNA molecules cause different rates of translation of their counterpart codons. This, in turn, produces a variable landscape of translational rate across each and every mRNA, with the dynamic formation and deformation of ribosomal queues being regulated by both tRNA availability and the rates of translation initiation and termination. In the present article, a range of examples of tRNA control of gene expression are reviewed, and the use of mathematical modelling to develop a predictive understanding of the consequences of that regulation is discussed and explained. These findings encourage a view that predicting the protein-synthesis rate of each mRNA requires a holistic understanding of how each stage of translation, including elongation, contributes to the overall protein-production rate.

Control and regulation of mRNA translation

“…However, as the Stansfield group point out in their paper [2], this artificial modularization is giving way to a more integrated global view of translation. As already discussed, the paper from the Bushell group [8] proposes a mechanism by which eIF4A2 acts to mediate miRNA gene regulation.…”

“…As early as the 1960s, it was recognized that translation required other protein factors in addition to ribosomes for efficient polypeptide synthesis [1]. In the salient model of translation, it is widely accepted that initiation is the rate-limiting step and point at which most control is exerted, although the papers from the Stansfield [2] and Tuller [3] groups in this issue highlight emerging data suggesting that this is not necessarily the case (see below).…”

“…With a particular focus on yeast models, they provide specific examples whereby Nature has used either tRNA abundance or tRNA modification to regulate gene expression. Such regulation by tRNAs is complex, and Gorgoni et al [2] provide an accessible overview as to how computational modelling can be applied to not only model translation increasingly realistically, but also to make quantitative predictions giving a fresh perspective and new insights into translational regulation of gene expression. Since it is probably a fair assessment that most scientists working on translational control are more familiar with the initiation pathway than with the intricacies of an elongation cycle, and since the actual mechanism by which codon usage controls gene expression is only slowly being worked out, misconceptions have become a widespread problem in this field.…”

“…[13][14][15]). In their review, Gorgoni et al [2] embrace both theoretical and experimental work on the control of mRNA translation at the level of the codon-anticodon interaction and present a compelling argument as to why creating predictive models of protein synthesis requires a holistic approach to modelling translational control. With a particular focus on yeast models, they provide specific examples whereby Nature has used either tRNA abundance or tRNA modification to regulate gene expression.…”

“…The articles by Tuller [3] and Stansfield [2] are based on a series of exciting recent studies on codon usage, translation elongation and their role in controlling gene expression. After many decades of concentrating on translation initiation as the major control point of translation, a spate of studies has recently emerged that reveal/confirm translation elongation is also an important point of control (e.g.…”