Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Regulation of protein synthesis by elongation control in health and disease

Funder Wellcome Charity-funded
Recipient organisation Medical Research Council Toxicology Unit
Funding £1.9M
Period Oct 2016 — Sept 2021

In plain English

AI plain-English summary

Cells build proteins in two stages: initiation, where the ribosome starts reading the genetic instructions, and elongation, where it adds amino acids one by one to grow the protein chain. For decades, scientists assumed initiation was the main control point. Recent work by this team shows that, under stress, elongation can take over as the dominant regulator—and that this shift matters in cancer and neurodegeneration. This matters because current drugs and therapies largely target initiation. If elongation control is what actually drives protein production in disease, then researchers have been looking at the wrong lever. The team has already linked elongation dysregulation to tumour growth and synaptic failure in neurons, but they do not yet know which messenger RNAs are controlled this way, what RNA sequences trigger it, or how transfer RNAs contribute. The project will map the full set of mRNAs under elongation control, identify the coding-region motifs that govern it, and build a computational model of elongation rate dynamics. This is fundamental science—there is no immediate clinical application. But understanding how cells reprogram their protein output under stress could eventually reveal new drug targets for cancers and neurodegenerative diseases where current treatments fall short.

View original technical description
Cells respond rapidly to external stress conditions by post-transcriptional control of gene expression; in particular, by the regulation of protein synthesis. Control of translation is achieved through modification of the translational machinery resulting in reprogramming of the translatome and synthesis of specific proteins required for stress protection/apoptosis. Recently, it has been shown that under certain pathophysiological conditions, modulation of translation rates via the elongation (rather than initiation) stage makes the major contribution to protein synthesis control. We have shown that this regulatory step is important in disease mechanisms, from tumorigenesis (Faller et al 2015 Nature) to failure of synaptic maintenance and neurodegeneration (Perretti et al 2015 Nature). Given this critical role for the control of the elongation stage of protein synthesis, we now propose to determine the full spectrum of mRNAs that are subject to this mode of regulation, including identification of the coding region RNA motifs required and the contribution of tRNAs in this process. These data will be used to generate a computational model of elongation rate control and provide novel insights into this mode of regulation that will be of broad relevance in understanding a range of pathological conditions.

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Researchers

Anne Willis (EPMC Awardee)

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Original classification

Collaborative Award in Science

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