The complex enzymology of mRNA decapping: Enzymes of four classes cleave pyrophosphate bonds

Abstract

The 5 0 ends of most RNAs are chemically modified to enable protection from nucleases. In bacteria, this is often achieved by keeping the triphosphate terminus originating from transcriptional initiation, while most eukaryotic mRNAs and small nuclear RNAs have a 5 0 !5 0 linked N 7 -methyl guanosine (m 7 G) cap added. Several other chemical modifications have been described at RNA 5 0 ends. Common to all modifications is the presence of at least one pyrophosphate bond. To enable RNA turnover, these chemical modifications at the RNA 5 0 end need to be reversible. Dependent on the direction of the RNA decay pathway (5 0 !3 0 or 3 0 !5 0 ), some enzymes cleave the 5 0 !5 0 cap linkage of intact RNAs to initiate decay, while others act as scavengers and hydrolyse the cap element of the remnants of the 3 0 !5 0 decay pathway. In eukaryotes, there is also a cap quality control pathway. Most enzymes involved in the cleavage of the RNA 5 0 ends are pyrophosphohydrolases, with only a few having (additional) 5 0 triphosphonucleotide hydrolase activities. Despite the identity of their enzyme activities, the enzymes belong to four different enzyme classes. Nudix hydrolases decap intact RNAs as part of the 5 0 !3 0 decay pathway, DXO family members mainly degrade faulty RNAs, members of the histidine triad (HIT) family are scavenger proteins, while an ApaH-like phosphatase is the major mRNA decay enzyme of trypanosomes, whose RNAs have a unique cap structure. Many novel cap structures and decapping enzymes have only recently been discovered, indicating that we are only beginning to understand the mechanisms of RNA decapping. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA Processing > Capping and 5 0 End Modifications K E Y W O R D S ApaH, decapping, HIT proteins, nudix, trypanosomes 1 | INTRODUCTIONSingle stranded RNAs with a free 5 0 monophosphate end are susceptible to rapid degradation. Transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) are stabilized by hairpin structures and by "hiding" their 5 0 ends within complex protein structures. All other RNA species avoid monophosphates at their 5 0 ends and instead carry chemical modifications arising either from the nucleotide initiating transcription or from further 5 0 end processing. These 5 0 end modifications can be as simple as a di-or triphosphate-often found in bacterial RNAs-or more complex like the 5 0 -5 0 linked N 7 -methyl guanosine (m 7 G) cap of eukaryotes or the NAD + cap found in both eukaryotes and bacteria. Despite the apparent differences, all chemical

miR-4293 Upregulates lncRNA WFDC21P by Directly Suppressing mRNA-Decapping Enzyme 2 to Promote Lung Carcinoma Proliferation

“…Several studies indicate that DCP2 appears to target distinct transcripts and the reported targets are almost all mRNAs. [40,45,46] However, we observed that DCP2 can bind to WFDC21P, a long non-coding RNA, to participate in cancer pathogenesis. We further clari ed that WFDC21P degradation played important roles in the tumorigenesis of lung carcinoma, and showed that DCP2 directly regulated by miR-4293, down-regulated WFDC21P expression.…”

A Novel NAD-RNA Decapping Pathway Discovered by Synthetic Light-Up NAD-RNAs

“…The discovery of NAD-capped RNAs in bacteria [3,8,9], mammalian cells, yeast [11,18] and plants [12,13] highlights the importance of studying the biogenesis, function, and removal of novel 5'-RNA modifications. The identification of new decapping enzymes can make important contributions to understanding the biological roles of NAD-capped RNAs [50].…”

Induction of RNA interference byC. elegansmitochondrial dysfunction via the DRH-1/RIG-I homologue RNA helicase and the EOL-1/RNA decapping enzyme

“…eol-1 encodes a decapping exoribonulease orthologous to yeast Rai1 and mammalian DXO ( Figure 2B). Mammalian DXO processes the 5' end of mRNA (Kramer and McLennan, 2019), including a decapping activity that removes the unmethylated guanosine cap and the first nucleotide (GpppN), the deNADing activity that removes the nicotinamide adenine dinucleotide (NAD) cap, the pyrophosphohydrolase (PPH) activity that releases pyrophosphate (PPi) from 5' triphosphorylated RNA, and 5'-3' exonuclease (5'-3' Exo) to degrade the entire RNA ( Figure 2C). The removal the m 7 G cap and subsequent degradation of mammalian mRNAs are directed by the decapping exoribonuclease DXO.…”