Abstract
The cytoplasmic abundance of mRNAs is strictly controlled through a balance of production and degradation. Whereas the control of mRNA synthesis through transcription has been well characterized, less is known about the regulation of mRNA turnover, and a consensus model explaining the wide variations in mRNA decay rates remains elusive. Here, we combine non-invasive transcriptome-wide mRNA production and stability measurements with selective and acute perturbations to demonstrate that mRNA degradation is tightly coupled to the regulation of translation, and that a competition between translation initiation and mRNA decay -but not codon optimality or elongation- is the major determinant of mRNA stability in yeast. Our refined measurements also reveal a remarkably dynamic transcriptome with an average mRNA half-life of only 4.8 min - much shorter than previously thought. Furthermore, global mRNA destabilization by inhibition of translation initiation induces a dose-dependent formation of processing bodies in which mRNAs can decay over time.
Highlights
Gene expression is the central process that drives all other cellular processes required for life
When this strategy is applied in a time-resolved manner, it enables the direct measurement of mRNA decay kinetics in an unperturbed system
All modifications targeted the problem of inefficient subtraction of newly synthesized mRNAs, which can result from inefficient chase of a metabolic label or low enrichment for labeled RNA during biotin-mRNA separation
Summary
Gene expression is the central process that drives all other cellular processes required for life. The amounts and modification states of the mRNA and protein gene products are what determine the identity, function and fate of a given cell. The abundances of both mRNAs and proteins are in turn determined kinetically by balancing both synthetic and degradative processes. At the mRNA level, we have a detailed understanding of both how mRNAs are made and how the individual steps of transcription, splicing and maturation are regulated. Less is known about the regulation of mRNA decay. Whereas individual steps of mRNA degradation have been determined, the question of what determines the stability of mRNAs across the transcriptome remains largely unanswered
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