![]() Moreover, the perturbations that have been employed to probe the relationship between translation and decay have the potential for significant secondary effects. However, the available experimental evidence for each of these models has mainly been gathered using specific reporter transcripts and methods to measure mRNA stability that can introduce unintended effects and thus might lead to non-physiological measurements of half-life as discussed below. Both of these models have supporting experimental evidence and are also not mutually exclusive. In the latter model, the stability of a given transcript would be determined by a competition between the eIF4F initiation complex and the decapping complex for the 5’ methylguanosine cap, and/or by ribosomes sterically blocking decay factors from the mRNA ( Beelman and Parker, 1994 Schwartz and Parker, 1999 Schwartz and Parker, 2000 LaGrandeur and Parker, 1999). Such a translation factor-protection model predicts that translation initiation, either directly or indirectly, competes with the RNA decay machinery. The second model arises from the observations that translation and decay are inversely related and posits that bound translation factors protect an mRNA from decay. Therefore, this stalled ribosome-triggered decay model centers on the process of translation elongation ( Presnyak et al., 2015 Radhakrishnan et al., 2016). It was proposed that slowly elongating ribosomes at suboptimal codons signal to the decay machinery to target the bound mRNAs for destruction. The first model originates from the observation that mRNA stability significantly correlates with codon usage. Two alternative models have been put forth to explain how mRNA decay is linked to translation (Figure 3A). While these pathways of mRNA degradation are well elucidated, their upstream regulators remain less clear and it is not well understood how the decision is made whether an mRNA continues to be translated or enters the decay pathway.įactors ranging from polyA tail length to mRNA structure have been proposed to affect global transcript stability but many models have been centered on how the process of translation regulates transcript lifetime. Removal of the cap structure is then followed by exonucleolytic digestion from the 5’ end of the mRNA by the cytoplasmic 5’ to 3’ exonuclease, Xrn1. mRNAs can either be degraded from the 3’ end by the exosome complex of 3’ to 5’ exonucleases or -what is thought to be more common in yeast- deadenylation is followed by removal of the 5’-methylguanosine cap by the decapping complex ( Muhlrad et al., 1994 Decker and Parker, 1993). This triggers degradation through one of two pathways. Whereas individual steps of mRNA degradation have been determined, the question of what determines the stability of mRNAs across the transcriptome remains largely unanswered.īulk mRNA degradation was shown to be initiated by the removal of the polyA tail ( Shyu et al., 1991 Muhlrad and Parker, 1992). However, less is known about the regulation of mRNA decay. 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. The abundances of both mRNAs and proteins are in turn determined kinetically by balancing both synthetic and degradative processes. The amounts and modification states of the mRNA and protein gene products are what ultimately determine the identity, function and fate of a given cell. Gene expression is the central process that drives all other cellular processes required for life. Furthermore, global mRNA destabilization by inhibition of translation initiation induces a dose-dependent formation of processing bodies in which mRNAs can decay over time. 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. 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. 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. The cytoplasmic abundance of mRNAs is strictly controlled through a balance of production and degradation. ![]()
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