The rRNA m 6 A methyltransferase METTL5 is involved in pluripotency and developmental programs.

Autor: Ignatova VV; Institute of Functional Epigenetics, Helmholtz Zentrum München (HMGU), Neuherberg 85764, Germany., Stolz P; Department of Biology II, Human Biology, and BioImaging, Ludwig-Maximilians Universität München, Munich 81377, Germany., Kaiser S; Chemical Faculty, Ludwig-Maximilians Universität München, Munich 81377, Germany., Gustafsson TH; University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA., Lastres PR; Institute of Functional Epigenetics, Helmholtz Zentrum München (HMGU), Neuherberg 85764, Germany., Sanz-Moreno A; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Cho YL; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Amarie OV; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Aguilar-Pimentel A; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Klein-Rodewald T; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Calzada-Wack J; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Becker L; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Marschall S; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Kraiger M; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Garrett L; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany.; Institute of Developmental Genetics, HMGU, Neuherberg 85764, Germany., Seisenberger C; Institute of Developmental Genetics, HMGU, Neuherberg 85764, Germany., Hölter SM; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany.; Institute of Developmental Genetics, HMGU, Neuherberg 85764, Germany., Borland K; Chemical Faculty, Ludwig-Maximilians Universität München, Munich 81377, Germany., Van De Logt E; Chemical Faculty, Ludwig-Maximilians Universität München, Munich 81377, Germany., Jansen PWTC; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, GA Nijmegen 6525, the Netherlands., Baltissen MP; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, GA Nijmegen 6525, the Netherlands., Valenta M; Institute of Functional Epigenetics, Helmholtz Zentrum München (HMGU), Neuherberg 85764, Germany., Vermeulen M; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, GA Nijmegen 6525, the Netherlands., Wurst W; Institute of Developmental Genetics, HMGU, Neuherberg 85764, Germany.; Chair of Developmental Genetics, Technische Universität München, Freising-Weihenstephan 85354, Germany.; Deutsches Institut für Neurodegenerative Erkrankungen (DZNE), Munich 81377, Germany.; Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Munich 81377, Germany., Gailus-Durner V; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Fuchs H; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany., Hrabe de Angelis M; German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany.; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 85354, Germany.; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany., Rando OJ; University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA., Kellner SM; Chemical Faculty, Ludwig-Maximilians Universität München, Munich 81377, Germany., Bultmann S; Department of Biology II, Human Biology, and BioImaging, Ludwig-Maximilians Universität München, Munich 81377, Germany., Schneider R; Institute of Functional Epigenetics, Helmholtz Zentrum München (HMGU), Neuherberg 85764, Germany.; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.; Faculty of Biology, Ludwig-Maximilians Universität München, Planegg-Martinsried 82152, Germany.
Jazyk: angličtina
Zdroj: Genes & development [Genes Dev] 2020 May 01; Vol. 34 (9-10), pp. 715-729. Date of Electronic Publication: 2020 Mar 26.
DOI: 10.1101/gad.333369.119
Abstrakt: 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 N 6 -methyladenosine (m 6 A) 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 m 6 A in 18S rRNA at position A 1832 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 m 6 A in rRNA in stemness, differentiation, development, and diseases.
(© 2020 Ignatova et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze: MEDLINE
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