CMTr cap-adjacent 2′-O-ribose mRNA methyltransferases are required for reward learning and mRNA localization to synapses

Haussmann, Irmgard U.; Wu, Yanying; Nallasivan, Mohanakarthik P.; Archer, Nathan; Bodi, Zsuzsanna; Hebenstreit, Daniel; Waddell, Scott; Fray, Rupert; Soller, Matthias

Abstract

Cap-adjacent nucleotides of animal, protist and viral mRNAs can be O-methylated at the 2`position of the ribose (cOMe). The functions of cOMe in animals, however, remain largely unknown. Here we show that the two cap methyltransferases (CMTr1 and CMTr2) of Drosophila can methylate the ribose of the first nucleotide in mRNA. Double-mutant flies lack cOMe but are viable. Consistent with prominent neuronal expression, they have a reward learning defect that can be rescued by conditional expression in mushroom body neurons before training. Among CMTr targets are cell adhesion and signaling molecules. Many are relevant for learning, and are also targets of Fragile X Mental Retardation Protein (FMRP). Like FMRP, cOMe is required for localization of untranslated mRNAs to synapses and enhances binding of the cap binding complex in the nucleus. Hence, our study reveals a mechanism to co-transcriptionally prime mRNAs by cOMe for localized protein synthesis at synapses.

• Journal Article Type: Article
• Acceptance Date: Jan 19, 2022
• Online Publication Date: Mar 8, 2022
• Publication Date: Mar 8, 2022
• Deposit Date: Feb 9, 2022
• Publicly Available Date: Mar 8, 2022
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Springer Science and Business Media LLC
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 1
• Article Number: 1209
• DOI: https://doi.org/10.1038/s41467-022-28549-5
• Keywords: General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/7414257
• Publisher URL: https://www.nature.com/articles/s41467-022-28549-5