The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation

Caraline Sepich-Poore, Zhong Zheng, Emily Schmitt, Kailong Wen, Zijie Scott Zhang, Xiao Long Cui, Qing Dai, Allen C. hu, Linda Zhang, Arantxa Sanchez Castillo, Haiyan Tan, Junmin Peng, Xiaoxi Zhuang, Chuan He*, Sigrid Nachtergaele*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Ribosomal RNAs (rRNAs) have long been known to carry chemical modifications, including 20O-methylation, pseudouridylation, N6-methyladenosine (m6A), and N6,6-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 m6A sites, and while the methyltransferase ZCCHC4 has been identified as the enzyme responsible for the 28S rRNA m6A modification, the methyltransferase responsible for the 18S rRNA m6A modification has remained unclear. Here, we show that the METTL5-TRMT112 methyltransferase complex installs the m6A 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 m6A 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 m6A in noncoding RNAs.

Original languageEnglish (US)
Article number101590
JournalJournal of Biological Chemistry
Volume298
Issue number3
DOIs
StatePublished - Mar 1 2022

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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