CMTr mediated 2'-O-ribose methylation status of cap adjacent-nucleotides across animals

Tom Dix, Irmgard Haussmann, Sarah Brivio, Mohanakarthik Ponnadai Nallasivan, Yavor Hadzhiev, Ferenc Müller, Jonathan Pettitt, Berndt Müller, Matthias Soller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Cap methyltransferases (CMTrs) O methylate the 2' position of the ribose (cOMe) of cap-adjacent nucleotides of animal, protist, and viral mRNAs. Animals generally have two CMTrs, whereas trypanosomes have three, and many viruses encode one in their genome. In the splice leader of mRNAs in trypanosomes, the first four nucleotides contain cOMe, but little is known about the status of cOMe in animals. Here, we show that cOMe is prominently present on the first two cap-adjacent nucleotides with species- and tissue-specific variations in Caenorhabditis elegans, honeybees, zebrafish, mouse, and human cell lines. In contrast, Drosophila contains cOMe primarily on the first cap-adjacent nucleotide. De novo RoseTTA modeling of CMTrs reveals close similarities of the overall structure and near identity for the catalytic tetrad, and for cap and cofactor binding for human, Drosophila and C. elegans CMTrs. Although viral CMTrs maintain the overall structure and catalytic tetrad, they have diverged in cap and cofactor binding. Consistent with the structural similarity, both CMTrs from Drosophila and humans methylate the first cap-adjacent nucleotide of an AGU consensus start. Because the second nucleotide is also methylated upon heat stress in Drosophila, these findings argue for regulated cOMe important for gene expression regulation.

Original languageEnglish
Pages (from-to)1377-1390
Number of pages14
Issue number10
Early online date15 Aug 2022
Publication statusPublished - Oct 2022

Bibliographical note

Funding Information:
We thank Mark Carrington and Nancy Standard for T. brucei total RNA, Jane Nimmo for honeybees, Caroline Chadwick for mouse tissue, Pawel Grzechnik for HEK293T cells, Roland Arnold for HCT116 cells, Rupert Fray for plasmids, and the National BioResource Project, Tokyo, Japan for the C. elegans CMTr2 strain. M.S. acknowledges funding from the Leverhulme Trust and the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/R002932/1), J.P. and B.M. from BBSRC (BB/T002859/1), and F.M. from the Wellcome Trust (106955/Z/ 15/Z).

Publisher Copyright:
© 2022 Dix et al.


  • 2’-O-ribose methylation
  • C. elegans
  • CMTr2
  • Drosophila
  • mRNA methylation


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