Abstract
mRNA translation and decay appear often intimately linked although the rules of this interplay are poorly understood. In this study, we combined our recent P-body transcriptome with transcriptomes obtained following silencing of broadly acting mRNA decay and repression factors, and with available CLIP and related data. This revealed the central role of GC content in mRNA fate, in terms of P-body localization, mRNA translation and mRNA stability: P-bodies contain mostly AU-rich mRNAs, which have a particular codon usage associated with a low protein yield; AU-rich and GC-rich transcripts tend to follow distinct decay pathways; and the targets of sequence-specific RBPs and miRNAs are also biased in terms of GC content. Altogether, these results suggest an integrated view of post-transcriptional control in human cells where most translation regulation is dedicated to inefficiently translated AU-rich mRNAs, whereas control at the level of 5' decay applies to optimally translated GC-rich mRNAs.
Highlights
Translation, storage, localization and decay of mRNAs in the cytoplasm are closely coupled processes, which are governed by a large number of RNA-binding proteins (RBPs) [1]
This analysis revealed the central role of GC content in mRNA fate, in terms of P-body localization, mRNA translation and mRNA decay
Compared to this impact of the GC content, sequence-specific RBPs and miRNAs appeared to have only modest additional effects on their bulk targets. These results lead to an integrated view of post-transcriptional control in human cells where most regulation at the level of translation is dedicated to AU-rich mRNAs, which have a limiting protein yield, whereas regulation at the level of 5’ decay applies to GC-rich mRNAs, whose translation is optimal
Summary
Translation, storage, localization and decay of mRNAs in the cytoplasm are closely coupled processes, which are governed by a large number of RNA-binding proteins (RBPs) [1]. These RBPs have to act in a coordinated manner to give rise to a proteome both coherent with cellular physiology and responsive to new cellular needs. The RBP PAT1B has been defined as an enhancer of decapping, as it interacts with DDX6, the LSM1-7 heptamer ring and the decapping complex in mammalian cells [9], while in yeast Pat1p activates Dcp directly [10] and its deletion results in deadenylated but capped intact mRNA [11,12]. The 5’-3’ exonuclease XRN1 decays RNAs following decapping by DCP1/2, a step triggered by deadenylation mediated by PAN2/3 and CCR4-NOT or by exosome activity [17]
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