Journal Article
. 2019 Jul; 47(15):7719-7733.
doi: 10.1093/nar/gkz619.

The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112

Nhan van Tran 1 Felix G M Ernst 2 Ben R Hawley 3 Christiane Zorbas 2 Nathalie Ulryck 1 Philipp Hackert 4 Katherine E Bohnsack 4 Markus T Bohnsack 4 Samie R Jaffrey 3 Marc Graille 1 Denis L J Lafontaine 2 
  • PMID: 31328227
  •     72 References
  •     52 citations


N6-methyladenosine (m6A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m6A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m6A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here, we identify METTL5 as the enzyme responsible for 18S rRNA m6A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5-TRMT112, supporting that its RNA-binding mode differs distinctly from that of other m6A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5-TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.

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Front Oncol, 2021 Feb 19; 10. PMID: 33598423    Free PMC article.
N6-methyladenosine as a Novel Regulator of Brain Physiology and Diseases.
Bing Han, Hong-Hong Yao.
Curr Med Sci, 2020 Jul 19; 40(3). PMID: 32681245
Metabolic Control of m6A RNA Modification.
Joohwan Kim, Gina Lee.
Metabolites, 2021 Feb 13; 11(2). PMID: 33573224    Free PMC article.
The RNA modification N6-methyladenosine as a novel regulator of the immune system.
Ziv Shulman, Noam Stern-Ginossar.
Nat Immunol, 2020 Apr 15; 21(5). PMID: 32284591
METTL16, Methyltransferase-Like Protein 16: Current Insights into Structure and Function.
Agnieszka Ruszkowska.
Int J Mol Sci, 2021 Mar 07; 22(4). PMID: 33671635    Free PMC article.
Construction and Comprehensive Analyses of a METTL5-Associated Prognostic Signature With Immune Implication in Lung Adenocarcinomas.
Sijin Sun, Kailun Fei, +8 authors, Jie He.
Front Genet, 2021 Mar 09; 11. PMID: 33679869    Free PMC article.
Enzymatic characterization of three human RNA adenosine methyltransferases reveals diverse substrate affinities and reaction optima.
Dan Yu, Gundeep Kaur, +2 authors, Xiaodong Cheng.
J Biol Chem, 2021 Jan 12;. PMID: 33428944    Free PMC article.
Dual effects of N6-methyladenosine on cancer progression and immunotherapy.
Hui Li, Hao Wu, +3 authors, Da Pang.
Mol Ther Nucleic Acids, 2021 Mar 20; 24. PMID: 33738136    Free PMC article.
The crosstalk between m6A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling.
Yanchun Zhao, Yunhao Chen, Mei Jin, Jin Wang.
Theranostics, 2021 Mar 24; 11(9). PMID: 33754077    Free PMC article.
RNA methylation in hematological malignancies and its interactions with other epigenetic modifications.
Lan Yao, Hua Yin, +5 authors, Qiuling Wu.
Leukemia, 2021 Mar 27; 35(5). PMID: 33767371    Free PMC article.
The role of RNA epigenetic modification in normal and malignant hematopoiesis.
Radovan Vasic, Yimeng Gao, Chengyang Liu, Stephanie Halene.
Curr Stem Cell Rep, 2021 Mar 30; 6(4). PMID: 33777659    Free PMC article.
Flipping the script: viral capitalization of RNA modifications.
Matthew T Sacco, Stacy M Horner.
Brief Funct Genomics, 2021 Jan 06; 20(2). PMID: 33401298    Free PMC article.
Role of RNA modifications in cancer.
Isaia Barbieri, Tony Kouzarides.
Nat Rev Cancer, 2020 Apr 18; 20(6). PMID: 32300195
N6-Methyladenosine Regulates Host Responses to Viral Infection.
Michael J McFadden, Stacy M Horner.
Trends Biochem Sci, 2020 Dec 15; 46(5). PMID: 33309325    Free PMC article.
Regulation of translation by methylation multiplicity of 18S rRNA.
Kuanqing Liu, Daniel A Santos, +4 authors, Benjamin P Tu.
Cell Rep, 2021 Mar 11; 34(10). PMID: 33691096    Free PMC article.
Chromatin and transcriptional regulation by reversible RNA methylation.
Jiangbo Wei, Chuan He.
Curr Opin Cell Biol, 2021 Mar 12; 70. PMID: 33706173    Free PMC article.
The Emerging Role of RNA Modifications in DNA Double-Strand Break Repair.
Sonia Jimeno, Fernando R Balestra, Pablo Huertas.
Front Mol Biosci, 2021 May 18; 8. PMID: 33996910    Free PMC article.