Abstract
The well established phenomenon of ribosome drop-off plays crucial roles in translational accuracy and nutrient starvation responses during protein translation. When cells are under stress conditions, such as amino acid starvation or aminoacyl-tRNA depletion due to a high level of recombinant protein expression, ribosome drop-off can substantially affect the efficiency of protein expression. Here we introduce a mathematical model that describes the effects of ribosome drop-off on the ribosome density along the mRNA and on the concomitant protein synthesis rate. Our results show that ribosome premature termination may lead to non-intuitive ribosome density profiles, such as a ribosome density which increases from the 5’ to the 3’ end. Importantly, the model predicts that the effects of ribosome drop-off on the translation rate are mRNA-specific, and we quantify their resilience to drop-off, showing that the mRNAs which present ribosome queues are much less affected by ribosome drop-off than those which do not. Moreover, among those mRNAs that do not present ribosome queues, resilience to drop-off correlates positively with the elongation rate, so that sequences using fast codons are expected to be less affected by ribosome drop-off. This result is consistent with a genome-wide analysis of S. cerevisiae, which reveals that under favourable growth conditions mRNAs coding for proteins involved in the translation machinery, known to be highly codon biased and using preferentially fast codons, are highly resilient to ribosome drop-off. Moreover, in physiological conditions, the translation rate of mRNAs coding for regulatory, stress-related proteins, is less resilient to ribosome drop-off. This model therefore allows analysis of variations in the translational efficiency of individual mRNAs by accounting for the full range of known ribosome behaviours, as well as explaining mRNA-specific variations in ribosome density emerging from ribosome profiling studies.
Highlights
Translational control of gene expression is acknowledged to be a key regulatory control point governing the relationship between messenger RNA (mRNA) expression levels, and the levels of the encoded polypeptide [1,2,3,4]
Ribosomes often drop off the messenger RNA molecules during the process of translation
To derive the density profiles for the stochastic model of ribosome drop-off, we start by writing the master equations in the standard mean-field approximation, i.e., neglecting correlations between neighbouring lattice sites: dri dt where we focus the discussion on the steady state, for which dri 1⁄4 0. dt Eq (5) gives access to the density profile, i.e the local density ρi for all sites i along the lattice
Summary
Translational control of gene expression is acknowledged to be a key regulatory control point governing the relationship between mRNA expression levels, and the levels of the encoded polypeptide [1,2,3,4]. One important aspect which has been considered only in a few models [18,19,20,21,22] is the fact that ribosomes are subject to premature translational abandonment, so-called ribosome dropoff events These can occur at non-stop codons anywhere in the open reading frame, and represent an energetically expensive form of translational error which results in the proteolytic degradation of the non-functional and partly made polypeptide. The existence of mechanisms to resolve such stalled complexes is necessary because cells devote a large percentage of their energy resources to produce ribosomes and must prevent them from becoming locked in non-productive stalled queues [24] Such pauses could be caused for example by depletion of aminoacyl-tRNA [20, 21], the incorporation of an amino acid from a non-cognate tRNA [26], the formation of a ‘non-stop’ translation complex or the presence of specific amino acid sequence motifs in the nascent polypeptide [24]. Rescuing ribosomes that have stalled in this way requires specific trans-acting factors, for example tmRNA and ArfA in bacteria, and Dom in eukaryotic systems [25, 27, 28]
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