New insights into decapping enzymes and selective mRNA decay

Abstract

Removal of the 5' end cap is a critical determinant controlling mRNA stability and efficient gene expression. Removal of the cap is exquisitely controlled by multiple direct and indirect regulators that influence association with the cap and the catalytic step. A subset of these factors directly stimulate activity of the decapping enzyme, while others influence remodeling of factors bound to mRNA and indirectly stimulate decapping. Furthermore, the components of the general decapping machinery can also be recruited by mRNA-specific regulatory proteins to activate decapping. The Nudix hydrolase, Dcp2, identified as a first decapping enzyme, cleaves capped mRNA and initiates 5'-3' degradation. Extensive studies on Dcp2 led to broad understanding of its activity and the regulation of transcript specific decapping and decay. Interestingly, seven additional Nudix proteins possess intrinsic decapping activity in vitro and at least two, Nudt16 and Nudt3, are decapping enzymes that regulate mRNA stability in cells. Furthermore, a new class of decapping proteins within the DXO family preferentially function on incompletely capped mRNAs. Importantly, it is now evident that each of the characterized decapping enzymes predominantly modulates only a subset of mRNAs, suggesting the existence of multiple decapping enzymes functioning in distinct cellular pathways. WIREs RNA 2017, 8:e1379. doi: 10.1002/wrna.1379 For further resources related to this article, please visit the WIREs website.

Figure 1. Schematic representation of the Nudix proteins with decapping activity

Nudix proteins with decapping activity are aligned relative to their Nudix motif. The human Dcp2 protein is schematically depicted at the top with the evolutionarily conserved domains, with Nudix Motif (red), Box A (green), Box B (blue) and regulatory domains encompassing the binding sites for Hedls (orange) and ubiquitin ligases (orange with stripes).

Figure 2. Schematic representation of the yeast Dcp2p decapping protein and its interacting partners

S. cerevisiae Dcp2p is schematically depicted with Nudix Motif (red), Box A (green), Box B (blue), cis-inhibitory element (grey) and binding sites for Dcp1p, Edc3p, Pat1p and Upf1p interacting proteins denoted along with their corresponding amino acid regions numbered.

Figure 3. A summary of the predominant cleavage site(s) within the cap triphosphate bridge for Nudix proteins with decapping activity

The position of the α, β and γ phosphates are shown with the cleave sites indicated by the arrow