SFB 1309
The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs
2020-03-26
Valentina V. Ignatova, Paul Stolz, Steffen Kaiser, Tobias H. Gustafsson, Palma Rico Lastres, Adrián Sanz-Moreno, Yi-Li Cho, Oana V. Amarie, Antonio Aguilar-Pimentel, Tanja Klein-Rodewald, Julia Calzada-Wack, Lore Becker, Susan Marschall, Markus Kraiger, Lillian Garrett, Claudia Seisenberger, Sabine M. Hölter, Kayla Borland, Erik Van De Logt, Pascal W.T.C. Jansen, Marijke P. Baltissen, Magdalena Valenta, Michiel Vermeulen, Wolfgang Wurst, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Oliver J. Rando, Stefanie M. Kellner, Sebastian Bultmann and Robert Schneider
Genes & Dev., 2020, 34, 715–729
Covalent chemical modifications of cellular RNAs directly impact all biological processes. However, our mechanistic understanding of the enzymes catalyzing these modifications, their substrates and biological functions, remains vague. Amongst RNA modifications N6-methyladenosine (m6A) is widespread and found in messenger (mRNA), ribosomal (rRNA), and noncoding RNAs. Here, we undertook a systematic screen to uncover new RNA methyltransferases. We demonstrate that the methyltransferase-like 5 (METTL5) protein catalyzes m6A in 18S rRNA at position A1832. We report that absence of Mettl5 in mouse embryonic stem cells (mESCs) results in a decrease in global translation rate, spontaneous loss of pluripotency, and compromised differentiation potential. METTL5-deficient mice are born at non-Mendelian rates and develop morphological and behavioral abnormalities. Importantly, mice lacking METTL5 recapitulate symptoms of patients with DNA variants in METTL5, thereby providing a new mouse disease model. Overall, our biochemical, molecular, and in vivo characterization highlights the importance of m6A in rRNA in stemness, differentiation, development, and diseases.
