2. Academic Validation
  3. The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs

The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs

  • Genes Dev. 2020 May 1;34(9-10):715-729. doi: 10.1101/gad.333369.119.
Valentina V Ignatova 1,  Paul Stolz 2,  Steffen Kaiser 3,  Tobias H Gustafsson 4,  Palma Rico Lastres 1,  Adrián Sanz-Moreno 5,  Yi-Li Cho 5,  Oana V Amarie 5,  Antonio Aguilar-Pimentel 5,  Tanja Klein-Rodewald 5,  Julia Calzada-Wack 5,  Lore Becker 5,  Susan Marschall 5,  Markus Kraiger 5,  Lillian Garrett 5 6,  Claudia Seisenberger 6,  Sabine M Hölter 5 6,  Kayla Borland 3,  Erik Van De Logt 3,  Pascal W T C Jansen 7,  Marijke P Baltissen 7,  Magdalena Valenta 1,  Michiel Vermeulen 7,  Wolfgang Wurst 6 8 9 10,  Valerie Gailus-Durner 5,  Helmut Fuchs 5,  Martin Hrabe de Angelis 5 11 12,  Oliver J Rando 4,  Stefanie M Kellner 3,  Sebastian Bultmann 2,  Robert Schneider 1 12 13
Affiliations

Affiliations

  • 1 Institute of Functional Epigenetics, Helmholtz Zentrum München (HMGU), Neuherberg 85764, Germany.
  • 2 Department of Biology II, Human Biology, and BioImaging, Ludwig-Maximilians Universität München, Munich 81377, Germany.
  • 3 Chemical Faculty, Ludwig-Maximilians Universität München, Munich 81377, Germany.
  • 4 University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • 5 German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany.
  • 6 Institute of Developmental Genetics, HMGU, Neuherberg 85764, Germany.
  • 7 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, GA Nijmegen 6525, the Netherlands.
  • 8 Chair of Developmental Genetics, Technische Universität München, Freising-Weihenstephan 85354, Germany.
  • 9 Deutsches Institut für Neurodegenerative Erkrankungen (DZNE), Munich 81377, Germany.
  • 10 Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Munich 81377, Germany.
  • 11 Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 85354, Germany.
  • 12 German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.
  • 13 Faculty of Biology, Ludwig-Maximilians Universität München, Planegg-Martinsried 82152, Germany.
PMID: 32217665 DOI: 10.1101/gad.333369.119
Abstract

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.

Keywords

m6A; methyltransferase; pluripotency.

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