METTL6 is a tRNA m3C methyltransferase that regulates pluripotency and tumor cell growth

Sci Adv. 2020 Aug 26;6(35):eaaz4551. doi: 10.1126/sciadv.aaz4551.

Valentina V Ignatova ¹, Steffen Kaiser ², Jessica Sook Yuin Ho ³ ⁴, Xinyang Bing ⁵, Paul Stolz ⁶, Ying Xim Tan ³, Chee Leng Lee ³, Florence Pik Hoon Gay ³, Palma Rico Lastres ¹, Raffaele Gerlini ⁷ ⁸, Birgit Rathkolb ⁷ ⁸ ⁹, Antonio Aguilar-Pimentel ⁷, Adrián Sanz-Moreno ⁷, Tanja Klein-Rodewald ⁷, Julia Calzada-Wack ⁷, Emil Ibragimov ¹, Magdalena Valenta ¹, Saulius Lukauskas ¹, Andrea Pavesi ³, Susan Marschall ⁷, Stefanie Leuchtenberger ⁷, Helmut Fuchs ⁷, Valerie Gailus-Durner ⁷, Martin Hrabe de Angelis ⁷ ⁸ ¹⁰, Sebastian Bultmann ⁶, Oliver J Rando ⁵, Ernesto Guccione ³ ¹¹, Stefanie M Kellner ², Robert Schneider ¹ ⁸ ¹²

Affiliations

1 Institute of Functional Epigenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
2 Chemical Faculty, Ludwig-Maximilians Universität München, Munich, Germany.
3 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
4 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5 University of Massachusetts Medical School, Worcester, MA 01605, USA.
6 Department of Biology II, Human Biology and BioImaging, Ludwig-Maximilians Universität München, Munich, Germany.
7 German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
8 German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
9 Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University München, Munich, Germany.
10 Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354 Freising, Germany.
11 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12 Faculty of Biology, Ludwig-Maximilians Universität München, Munich, Germany.

PMID: 32923617 DOI: 10.1126/sciadv.aaz4551

Abstract

Recently, covalent modifications of RNA, such as methylation, have emerged as key regulators of all aspects of RNA biology and have been implicated in numerous diseases, for instance, Cancer. Here, we undertook a combination of in vitro and in vivo screens to test 78 potential methyltransferases for their roles in hepatocellular carcinoma (HCC) cell proliferation. We identified methyltransferase-like protein 6 (METTL6) as a crucial regulator of tumor cell growth. We show that METTL6 is a bona fide transfer RNA (tRNA) methyltransferase, catalyzing the formation of 3-methylcytidine at C32 of specific serine tRNA isoacceptors. Deletion of Mettl6 in mouse stem cells results in changes in ribosome occupancy and RNA levels, as well as impaired pluripotency. In mice, Mettl6 knockout results in reduced energy expenditure. We reveal a previously unknown pathway in the maintenance of translation efficiency with a role in maintaining stem cell self-renewal, as well as impacting tumor cell growth profoundly.

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