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

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The 5′ 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′→5′ linked N7‐methyl guanosine (m7G) cap added. Several other chemical modifications have been described at RNA 5′ 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′ end need to be reversible. Dependent on the direction of the RNA decay pathway (5′→3′ or 3′→5′), some enzymes cleave the 5′→5′ cap linkage of intact RNAs to initiate decay, while others act as scavengers and hydrolyse the cap element of the remnants of the 3′→5′ decay pathway. In eukaryotes, there is also a cap quality control pathway. Most enzymes involved in the cleavage of the RNA 5′ ends are pyrophosphohydrolases, with only a few having (additional) 5′ 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′→3′ 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′ End Modifications
The special mRNA metabolism of trypanosomes. (a) Polycistronic transcription and processing by trans‐splicing. (b) The trypanosome cap4
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Summary of the decapping enzymes discussed in this work with their respective substrates and cleavage sites. Cleavage sites with no evidence for in vivo relevance were excluded. To the best of our knowledge, there is currently no known example of a cap3 (a cap modified on the first three transcribed nucleotides)
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mRNA decay pathways in bacteria and eukaryotes
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RNA Processing > Capping and 5′ End Modifications
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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