Trypanosome mRNA recapping is triggered by hypermethylation originating from cap 4.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

RNA Caps*/metabolism ; RNA Caps*/genetics ; Trypanosoma brucei brucei*/genetics ; RNA, Messenger*/metabolism ; RNA, Messenger*/genetics ; Nucleotidyltransferases*/metabolism ; Nucleotidyltransferases*/genetics ; Protozoan Proteins*/genetics ; Protozoan Proteins*/metabolism; Methylation ; Methyltransferases/metabolism ; Methyltransferases/genetics ; Cytoplasm/metabolism ; Adenosine/analogs & derivatives ; Adenosine/metabolism ; Adenosine/genetics

RNA methylation adjacent to the 5' cap plays a critical role in controlling mRNA stability and protein synthesis. In trypanosomes the 5'-terminus of mRNA is protected by hypermethylated cap 4. Trypanosomes encode a cytoplasmic recapping enzyme TbCe1 which possesses an RNA kinase and guanylyltransferase activities that can convert decapped 5'-monophosphate-terminated pRNA into GpppRNA. Here, we demonstrated that the RNA kinase activity is stimulated by two orders of magnitude on a hypermethylated pRNA derived from cap 4. The N6, N6-2'-O trimethyladenosine modification on the first nucleotide was primarily accountable for enhancing both the RNA kinase and the guanylyltransferase activity of TbCe1. In contrast, N6 methyladenosine severely inhibits the guanylyltransferase activity of the mammalian capping enzyme. Furthermore, we showed that TbCmt1 cap (guanine N7) methyltransferase was localized in the cytoplasm, and its activity was also stimulated by hypermethylation at 2'-O ribose, suggesting that TbCe1 and TbCmt1 act together as a recapping enzyme to regenerate translatable mRNA from decapped mRNA. Our result establishes the functional role of cap 4 hypermethylation in recruitment and activation of mRNA recapping pathway. Methylation status at the 5'-end of transcripts could serve as a chemical landmark to selectively regulate the level of functional mRNA by recapping enzymes.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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21K06984 KAKENHI; University of Tsukuba

0 (RNA Caps)
0 (RNA, Messenger)
EC 2.7.7.- (Nucleotidyltransferases)
0 (Protozoan Proteins)
EC 2.1.1.- (Methyltransferases)
EC 2.7.7.- (guanylyltransferase)
EC 2.1.1.56 (mRNA (guanine(N7))-methyltransferase)
K72T3FS567 (Adenosine)

Date Created: 20240716 Date Completed: 20240923 Latest Revision: 20240925

20240925

PMC11417388

10.1093/nar/gkae614

39011881