School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Department of Life Science, Faculty of Health, Education and Life Sciences, Birmingham City University, Birmingham, B15 3TN, UK.
Nat Commun. 2022 Mar 8;13(1):1209. doi: 10.1038/s41467-022-28549-5.
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.
动物、原生动物和病毒 mRNA 的帽邻近核苷酸可以在核糖的 2'位被 O-甲基化（cOMe）。然而，cOMe 在动物中的功能在很大程度上仍然未知。在这里，我们显示果蝇中的两种帽甲基转移酶（CMTr1 和 CMTr2）可以甲基化 mRNA 中第一个核苷酸的核糖。双突变果蝇缺乏 cOMe，但仍具有活力。与明显的神经元表达一致，它们存在奖励学习缺陷，可以通过在训练前在蘑菇体神经元中进行条件表达来挽救。在 CMTr 靶标中包括细胞粘附和信号分子。许多与学习有关，也是脆性 X 智力迟钝蛋白 (FMRP) 的靶标。与 FMRP 一样，cOMe 对于未翻译的 mRNA 定位到突触以及增强核中帽结合复合物的结合都是必需的。因此，我们的研究揭示了一种通过 cOMe 对 mRNA 进行共转录起始的机制，以便在突触处进行本地化蛋白质合成。
