Differential m 6 A, m 6 A m, and m 1 A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm

Mol Cell. 2018 Sep 20;71(6):973-985.e5. doi: 10.1016/j.molcel.2018.08.011. Epub 2018 Sep 6.

Abstract

FTO, the first RNA demethylase discovered, mediates the demethylation of internal N6-methyladenosine (m6A) and N6, 2-O-dimethyladenosine (m6Am) at the +1 position from the 5' cap in mRNA. Here we demonstrate that the cellular distribution of FTO is distinct among different cell lines, affecting the access of FTO to different RNA substrates. We find that FTO binds multiple RNA species, including mRNA, snRNA, and tRNA, and can demethylate internal m6A and cap m6Am in mRNA, internal m6A in U6 RNA, internal and cap m6Am in snRNAs, and N1-methyladenosine (m1A) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal m6A than the ones with cap m6Am in the tested cells. We also show that FTO can directly repress translation by catalyzing m1A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m6A and m6Am in mRNA and snRNA as well as m1A in tRNA.

Keywords: FTO; cap m(6)A(m); cytoplasmic demethylation; m(6)A; nuclear m(6)A demethylation; snRNA demethylation; tRNA m(1)A demethylation; translation regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3-L1 Cells
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / physiology*
  • Animals
  • Cell Nucleus
  • Cytoplasm
  • Demethylation
  • Gene Expression / genetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Methylation
  • Mice
  • RNA Processing, Post-Transcriptional / physiology
  • RNA, Messenger / metabolism
  • RNA, Small Nuclear / metabolism
  • RNA, Transfer / metabolism

Substances

  • RNA, Messenger
  • RNA, Small Nuclear
  • U6 small nuclear RNA
  • N6-methyladenosine (m6A)
  • RNA, Transfer
  • FTO protein, mouse
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Adenosine