The METTL5-TRMT112 N 6 -methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation.

Autor:	Sepich-Poore C; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA; University of Chicago Medical Scientist Training Program, Chicago, Illinois, USA., Zheng Z; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA., Schmitt E; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA., Wen K; Department of Neurobiology, University of Chicago, Chicago, Illinois, USA., Zhang ZS; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA., Cui XL; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA., Dai Q; Department of Chemistry, University of Chicago, Chicago, Illinois, USA., Zhu AC; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA; University of Chicago Medical Scientist Training Program, Chicago, Illinois, USA., Zhang L; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA., Sanchez Castillo A; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA., Tan H; Center for Proteomics and Metabolomics, St Jude Children's Research Hospital, Memphis, Tennessee, USA; Departments of Structural Biology and Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA., Peng J; Center for Proteomics and Metabolomics, St Jude Children's Research Hospital, Memphis, Tennessee, USA; Departments of Structural Biology and Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA., Zhuang X; Department of Neurobiology, University of Chicago, Chicago, Illinois, USA., He C; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois, USA. Electronic address: chuanhe@uchicago.edu., Nachtergaele S; Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA. Electronic address: sigrid.nachtergaele@yale.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Mar; Vol. 298 (3), pp. 101590. Date of Electronic Publication: 2022 Jan 14.
DOI:	10.1016/j.jbc.2022.101590
Abstrakt:	Ribosomal RNAs (rRNAs) have long been known to carry chemical modifications, including 2'O-methylation, pseudouridylation, N 6 -methyladenosine (m 6 A), and N 6,6- dimethyladenosine. While the functions of many of these modifications are unclear, some are highly conserved and occur in regions of the ribosome critical for mRNA decoding. Both 28S rRNA and 18S rRNA carry single m 6 A sites, and while the methyltransferase ZCCHC4 has been identified as the enzyme responsible for the 28S rRNA m 6 A modification, the methyltransferase responsible for the 18S rRNA m 6 A modification has remained unclear. Here, we show that the METTL5-TRMT112 methyltransferase complex installs the m 6 A modification at position 1832 of human 18S rRNA. Our work supports findings that TRMT112 is required for METTL5 stability and reveals that human METTL5 mutations associated with microcephaly and intellectual disability disrupt this interaction. We show that loss of METTL5 in human cancer cell lines and in mice regulates gene expression at the translational level; additionally, Mettl5 knockout mice display reduced body size and evidence of metabolic defects. While recent work has focused heavily on m 6 A modifications in mRNA and their roles in mRNA processing and translation, we demonstrate here that deorphanizing putative methyltransferase enzymes can reveal previously unappreciated regulatory roles for m 6 A in noncoding RNAs. Competing Interests: Conflict of interest C. H. is a scientific founder and a member of the scientific advisory board of Accent Therapeutics, Inc. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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