The regulation of mRNA stability in mammalian cells: 2.0

Abstract

Messenger RNA decay is an essential step in gene expression to set mRNA abundance in the cytoplasm. The binding of proteins and/or noncoding RNAs to specific recognition sequences or secondary structures within mRNAs dictates mRNA decay rates by recruiting specific enzyme complexes that perform the destruction processes. Often, the cell coordinates the degradation or stabilization of functional subsets of mRNAs encoding proteins collectively required for a biological process. As well, extrinsic or intrinsic stimuli activate signal transduction pathways that modify the mRNA decay machinery with consequent effects on decay rates and mRNA abundance. This review is an update to our 2001 Gene review on mRNA stability in mammalian cells, and we survey the enormous progress made over the past decade.

Pre-mRNA processing includes N6 methylation of adenosine residues that are retained in mRNA exons and the fallacy of “RNA epigenetics”

“…Biochemists have known for years that different mRNAs in eukaryotic cells exhibit different turnover times (Parker and Song 2004;Garneau et al 2007;Song et al 2010;Schoenberg and Maquat 2012;Wu and Brewer 2012). The main function for most of the m 6 A residues in mRNA in mammalian cells appears to be increasing mRNA turnover since a higher m 6 A content in an mRNA molecule correlates with faster turnover (Ke et al 2017 (Ke et al 2017).…”

Pcsk9

“…Structurally unstable mRNAs are typically characterized by a high AU content in their 3′-UTR. 98 At the extreme end of 1.3-kb long 3′-UTR of human PCSK9, mRNA is an island of ≈120 nts (nts 575-3692; NM_174936.3), which exhibits 71% AU content, contains 2 AUUUA canonical AU-rich elements commonly associated with mRNA instability, and is relatively conserved among primates and rodents. The relevance of this AU island in mRNA stability remains to be functionally determined.…”

Mathematical modeling of combinatorial regulation suggests that apparent positive regulation of targets by miRNA could be an artifact resulting from competition for mRNA

“…Translational repression by miRNA can come about via multiple methods (Liu et al 2005;Chekulaeva and Filipowicz 2009;McDaneld 2009;Fabian et al 2010;Huntzinger and Izaurralde 2011), such as (i) by blocking the initiation site; (ii) by hindering the eIF4E function or its recruitment to 5 ′ cap of the target; (iii) by slowing down elongation owing to ribosome fall off or promotion of premature termination; or (iv) by translocation of the miRNA-target complex to processing bodies (P-bodies). The predominant action of miRNA on its targets is destabilization of target transcripts (Guo et al 2010), which occurs through multiple mechanisms including the slicer activity of Argonaute 2, deadenylation/decapping-dependent pathways, and coordinated regulation by RNA-binding proteins and miRNA (Fabian et al 2010;Huntzinger and Izaurralde 2011;Wu and Brewer 2012). miRNA activity has been termed as catalytic because one miRNA regulates more than one target strand.…”