Multiple mRNA Decapping Enzymes in Mammalian Cells

Abstract

SUMMARY Regulation of RNA degradation plays an important role in the control of gene expression. One mechanism of eukaryotic mRNA decay proceeds through an initial deadenylation followed by 5′-end decapping and exonucleolytic decay. Dcp2 is currently believed to be the only cytoplasmic decapping enzyme responsible for decapping of all mRNAs. Here we report that Dcp2 protein modestly contributes to bulk mRNA decay and surprisingly is not detectable in a subset of mouse and human tissues. Consistent with these findings, a hypomorphic knockout of Dcp2 had no adverse consequences in mice. In contrast, the previously reported Xenopus nucleolar decapping enzyme, Nudt16, is an ubiquitous cytoplasmic decapping enzyme in mammalian cells. Like Dcp2, Nudt16 also regulates the stability of a subset of mRNAs including a member of the motin family of proteins involved in angiogenesis, Angiomotin-like 2. These data demonstrate mammalian cells possess multiple mRNA decapping enzymes, including Nudt16 to regulate mRNA turnover.

Multiple Nudix family proteins possess mRNA decapping activity

“…Our recent demonstration that Nudt16 is a second decapping enzyme in mammals (Song et al 2010) and the identification of six additional Nudix proteins with decapping activity in this study raised the intriguing possibility of whether Nudix proteins in other organisms also contain decapping activity. Search of the yeast Saccharomyces cerevisiae database revealed the presence of six Nudix proteins, including the Dcp2 decapping enzyme.…”

“…In the 3 ′ decay pathway, a multi-subunit exosome complex degrades the mRNA in a 3 ′ -to-5 ′ direction (Mitchell et al 1997;Anderson and Parker 1998), and the resulting cap dinucleotide is subsequently hydrolyzed by the scavenger decapping enzyme, DcpS (Wang and Kiledjian 2001;Liu et al 2002). In the 5 ′ decay pathway, the monomethyl guanosine (m 7 G) mRNA cap is cleaved to generate a 5 ′ -monophosphate RNA (Dunckley and Parker 1999;Lykke-Andersen 2002;van Dijk et al 2002;Wang et al 2002;Song et al 2010) that is subsequently degraded by the 5 ′ -to-3 ′ exoribonuclease Xrn1 (Decker and Parker 1993;Hsu and Stevens 1993).…”

“…Removal of 5 ′ -cap structure is carried out by at least two mRNA decapping enzymes, Dcp2 (Dunckley and Parker 1999;Lykke-Andersen 2002;van Dijk et al 2002;Wang et al 2002) and Nudt16 (Song et al 2010). Dcp2 activity is highly regulated, and numerous proteins have been identified to colocalize with Dcp2 in cytoplasmic foci termed P-bodies (Franks and Lykke-Andersen 2008).…”

“…Nudt16 was initially identified in Xenopus as a nucleolar decapping enzyme that specifically binds the U8 snoRNA (Tomasevic and Peculis 1999;Ghosh et al 2004). It was subsequently shown to be a cytoplasmic protein in mammalian cells and involved in mRNA decapping (Song et al 2010). A comparison of the two decapping proteins revealed that they are both differentially used in specified mRNA decay processes: NMD preferentially uses Dcp2 rather than Nudt16; Dcp2 and Nudt16 are redundant in microRNA-mediated silencing; and Dcp2 and Nudt16 are differentially used for different ARE-mRNA decay (Li et al 2011).…”

“…A comparison of the two decapping proteins revealed that they are both differentially used in specified mRNA decay processes: NMD preferentially uses Dcp2 rather than Nudt16; Dcp2 and Nudt16 are redundant in microRNA-mediated silencing; and Dcp2 and Nudt16 are differentially used for different ARE-mRNA decay (Li et al 2011). Surprisingly, both Dcp2 and Nudt16 regulate the stability of only a subset of mRNA transcripts (Song et al 2010;Li et al 2011), indicating that there may be additional heretofore uncharacterized decapping enzyme(s).…”