Differential m⁶A, m⁶A_m, and m¹A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm.

FTO, the first RNA demethylase discovered, mediates the demethylation of internal N⁶-methyladenosine (m⁶A) and N⁶, 2-O-dimethyladenosine (m⁶A_m) 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 m⁶A_m in mRNA, internal m⁶A in U6 RNA, internal and cap m⁶A_m 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 m⁶A_m 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 m⁶A_m in mRNA and snRNA as well as m¹A in tRNA. Copyright © 2018 Elsevier Inc. All rights reserved.

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