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

Differential m6A, m6Am, and m1A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm.

Author information

1
Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA.
2
Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Institute of Natural Sciences, Westlake Institute for Advanced Study, Westlake University, 18 Shilongshan Road, Hangzhou 310064, China.
3
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
4
Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway Institute of Basic Medical Sciences, University of Oslo, PO Box 1018 Blindern, 0315 Oslo, Norway.
5
Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
6
Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.

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

PMID:
30197295
PMCID:
PMC6151148
[Available on 2019-09-20]
DOI:
10.1016/j.molcel.2018.08.011
[Indexed for MEDLINE]

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