S-Adenosylmethionine Synthesis Is Regulated by Selective N 6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1

Cell Rep. 2017 Dec 19;21(12):3354-3363. doi: 10.1016/j.celrep.2017.11.092.

Abstract

S-adenosylmethionine (SAM) is an important metabolite as a methyl-group donor in DNA and histone methylation, tuning regulation of gene expression. Appropriate intracellular SAM levels must be maintained, because methyltransferase reaction rates can be limited by SAM availability. In response to SAM depletion, MAT2A, which encodes a ubiquitous mammalian methionine adenosyltransferase isozyme, was upregulated through mRNA stabilization. SAM-depletion reduced N6-methyladenosine (m6A) in the 3' UTR of MAT2A. In vitro reactions using recombinant METTL16 revealed multiple, conserved methylation targets in the 3' UTR. Knockdown of METTL16 and the m6A reader YTHDC1 abolished SAM-responsive regulation of MAT2A. Mutations of the target adenine sites of METTL16 within the 3' UTR revealed that these m6As were redundantly required for regulation. MAT2A mRNA methylation by METTL16 is read by YTHDC1, and we suggest that this allows cells to monitor and maintain intracellular SAM levels.

Keywords: MAT2A; METTL16; RNA; RNA degradation; S-adenosylmethionine; YTHDC1; cycloleucine; methionine adenosyltransferase; methyladenosine; untranslated region.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Methionine Adenosyltransferase / genetics*
  • Methionine Adenosyltransferase / metabolism
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • RNA Processing, Post-Transcriptional
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism*
  • RNA Stability*
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • S-Adenosylmethionine / metabolism*

Substances

  • 3' Untranslated Regions
  • Nerve Tissue Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • YTHDC1 protein, human
  • S-Adenosylmethionine
  • METTL16 protein, human
  • Methyltransferases
  • MAT2A protein, human
  • Methionine Adenosyltransferase