Molecular Cell
Volume 71, Issue 6, 20 September 2018, Pages 973-985.e5
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Article
Differential m6A, m6Am, and m1A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm

https://doi.org/10.1016/j.molcel.2018.08.011Get rights and content
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Highlights

  • FTO mediates both internal m6A and cap m6Am demethylation of polyadenylated RNA

  • FTO exhibits differential substrate preferences in nucleus versus cytoplasm

  • Internal mRNA m6A demethylation by FTO correlates with transcript level changes

  • FTO affects snRNA m6A and m6Am levels and mediates tRNA m1A demethylation

Summary

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
nuclear m6A demethylation
cytoplasmic demethylation
m6A
cap m6Am
tRNA m1A demethylation
translation regulation
snRNA demethylation

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