2. Academic Validation
  3. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA

The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA

  • Nucleic Acids Res. 2020 Jan 24;48(2):830-846. doi: 10.1093/nar/gkz1147.
Rita Pinto 1,  Cathrine B Vågbø 2 3,  Magnus E Jakobsson 4,  Yeji Kim 5 6,  Marijke P Baltissen 7,  Marie-Françoise O'Donohue 8,  Ulises H Guzmán 4,  Jędrzej M Małecki 1,  Jie Wu 5 6,  Finn Kirpekar 9,  Jesper V Olsen 4,  Pierre-Emmanuel Gleizes 8,  Michiel Vermeulen 7,  Sebastian A Leidel 5 6,  Geir Slupphaug 2 3,  Pål Ø Falnes 1
Affiliations

Affiliations

  • 1 Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo 0316, Norway.
  • 2 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, NO-7491 Trondheim, Norway.
  • 3 Proteomics and Modomics Experimental Core (PROMEC), NTNU and the Central Norway Regional Health Authority, NO-7491 Trondheim, Norway.
  • 4 Proteomics Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research (NNF-CPR), University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
  • 5 Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany.
  • 6 Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.
  • 7 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen 6500 HB, The Netherlands.
  • 8 Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France.
  • 9 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
PMID: 31799605 DOI: 10.1093/nar/gkz1147
Abstract

RNA methylations are essential both for RNA structure and function, and are introduced by a number of distinct methyltransferases (MTases). In recent years, N6-methyladenosine (m6A) modification of eukaryotic mRNA has been subject to intense studies, and it has been demonstrated that m6A is a reversible modification that regulates several aspects of mRNA function. However, m6A is also found in other RNAs, such as mammalian 18S and 28S ribosomal RNAs (rRNAs), but the responsible MTases have remained elusive. 28S rRNA carries a single m6A modification, found at position A4220 (alternatively referred to as A4190) within a stem-loop structure, and here we show that the MTase ZCCHC4 is the Enzyme responsible for introducing this modification. Accordingly, we found that ZCCHC4 localises to nucleoli, the site of ribosome assembly, and that proteins involved in RNA metabolism are overrepresented in the ZCCHC4 interactome. Interestingly, the absence of m6A4220 perturbs codon-specific translation dynamics and shifts gene expression at the translational level. In summary, we establish ZCCHC4 as the Enzyme responsible for m6A modification of human 28S rRNA, and demonstrate its functional significance in mRNA translation.

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