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PMID: 23653210 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA.

Nature communications ·Vol. 4 ·2013-00-00 ·Pages 1798

Fu Y, Jia G, Pang X, Wang RN, Wang X, Li CJ, Smemo S, Dai Q, Bailey KA, Nobrega MA, Han KL, Cui Q, He C

Abstract

N(6)-methyladenosine is a prevalent internal modification in messenger RNA and non-coding RNA affecting various cellular pathways. Here we report the discovery of two additional modifications, N(6)-hydroxymethyladenosine (hm(6)A) and N(6)-formyladenosine (f(6)A), in mammalian messenger RNA. We show that Fe(II)- and α-ketoglutarate-dependent fat mass and obesity-associated (FTO) protein oxidize N(6)-methyladenosine to generate N(6)-hydroxymethyladenosine as an intermediate modification, and N(6)-formyladenosine as a further oxidized product. N(6)-hydroxymethyladenosine and N(6)-formyladenosine have half-life times of ~3 h in aqueous solution under physiological relevant conditions, and are present in isolated messenger RNA from human cells as well as mouse tissues. These previously unknown modifications derived from the prevalent N(6)-methyladenosine in messenger RNA, formed through oxidative RNA demethylation, may dynamically modulate RNA-protein interactions to affect gene expression regulation.

MeSH Terms
Adenosine/analogs & derivatives,chemistry,metabolism Alpha-Ketoglutarate-Dependent Dioxygenase FTO Animals Humans Kinetics Mammals/metabolism Methylation Mice Models, Biological Molecular Dynamics Simulation Oxidation-Reduction Protein Binding Proteins/metabolism RNA/chemistry,metabolism RNA, Messenger/genetics,metabolism RNA-Binding Proteins/metabolism Substrate Specificity
Chemicals
Proteins RNA, Messenger RNA-Binding Proteins RNA N(6)-hydroxymethyladenosine Alpha-Ketoglutarate-Dependent Dioxygenase FTO FTO protein, human Adenosine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Fu Ye
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
Jia Guifang
Pang Xueqin
Wang Richard N
Wang Xiao
Li Charles J
Smemo Scott
Dai Qing
Bailey Kathleen A
Nobrega Marcelo A
Han Ke-Li
Cui Qiang
He Chuan
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms2822
Published
2013-00-00
Pages
1798
Language
English
Region
England
NLM ID
101528555
PMCID
PMC3658177
Subset
IM
Grants
NIGMS NIH HHS · GM084028 · United States
NHGRI NIH HHS · K01 HG006699 · United States
NIGMS NIH HHS · R01 GM088599 · United States
NIGMS NIH HHS · R01 GM084028 · United States
NIGMS NIH HHS · GM088599 · United States
NIGMS NIH HHS · GM071440 · United States
NHLBI NIH HHS · T32 HL007381 · United States
NIGMS NIH HHS · R01 GM071440 · United States
External Links
PubMed source DOI: 10.1038/ncomms2822 PMC Full Text View journal details
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