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How to stop an mRNA?

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To prevent the continued expression of its protein product, an mRNA must, at some point be destroyed.

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The key to understanding how mRNA degrade, therefore, is to understand how they are translated.

Messenger RNA (mRNA) degradation plays a critical role in regulating transcript levels in the cell and is a major control point for modulating gene expression. Degradation of most mRNAs is thought to initiate by removal of the 3’ poly(A) tail (deadenylation), followed by cleavage of the 5’ 7mGpppN cap (decapping) and exonucleolytic degradation of the mRNA body in a 5’-3’ direction. Despite being targeted by a common decay pathway, turnover rates for individual yeast mRNAs differ dramatically with half-lives ranging from <1 minute to 60 minutes or greater. RNA features that influence transcript stability have long been sought, and some sequence and/or structural elements located within 5’ and 3’ untranslated regions (UTRs) have been implicated in contributing to the decay of a subset of mRNAs. However, these features regulate mRNA stability predominantly in a transcript-specific manner through binding of regulatory factors and cannot account for the wide variation in half-lives observed across the entire transcriptome. Therefore, it seems likely that additional and more general features which act to modulate transcript stability could exist within mRNAs. In our current work, we find that codon usage is the critical determinant of mRNA half-life.

 

A prevailing zeitgeist has been that synonymous codon substitutions are silent, having no bearing on gene function. Antithetically, a growing body of literature implicates that synonymous codons are recognized by the translational apparatus differently. This concept has been referred to as codon optimality. Conceptually, codon optimality is a scale that reflects the balance between the supply of charged tRNA molecules in the cytoplasmic pool and the demand of tRNA usage by translating ribosomes, representing a measure of translation efficiency. Critically, optimal codons are postulated to be decoded faster by the ribosome because their cognate tRNA are abundant, while non-optimal codons, are hypothesized to be read slower because their tRNA concentration is limited. Therefore, codon optimality is hypothesized to play an important role in modulation of translation elongation rates and the kinetics of protein synthesis. While codon optimality has been hypothesized to impact mRNA translation rates, there is little direct biological evidence that synonymous codons have broad and general effects on gene expression.

 

It is important to note that codon optimality is not equal to either the terms codon usage or codon bias. Codon usage/bias is indicative of how frequently a codon is used within the genome. Codon optimality is a measure of how efficiently the codon is read by the ribosome - optimal codons and non-optimal codons can be both rare or frequent in the genome.

 

We have demonstrated that codon optimality is the major determinate of mRNA stability in budding yeast. First, global analysis of RNA decay rates reveals that mRNA half-life correlates with optimal codon content. Most stable mRNAs demonstrate a strong preference towards the inclusion of optimal codons within their coding regions, while most unstable mRNAs harbor non-optimal codons. Second, we demonstrate that substitution of optimal codons with synonymous, non-optimal codons results in a dramatic destabilization of the mRNA and that the converse replacement leads to a significant increase in mRNA stability. Third, we observe tightly coordinated optimal codon content in genes encoding proteins with common physiological function. We hypothesize that this finding explains the previously observed similarity in mRNA decay rates for these gene families. Taken together, our data suggest that there is evolutionary pressure on protein coding regions to coordinate gene expression at the level of protein synthesis and mRNA decay.