title: FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA.
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.
authors: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors: Ye
authors: Y
authors: Fu
authors: Guifang
authors: G
authors: Jia
authors: Xueqin
authors: X
authors: Pang
authors: Richard N
authors: RN
authors: Wang
authors: Xiao
authors: X
authors: Wang
authors: Charles J
authors: CJ
authors: Li
authors: Scott
authors: S
authors: Smemo
authors: Qing
authors: Q
authors: Dai
authors: Kathleen A
authors: KA
authors: Bailey
authors: Marcelo A
authors: MA
authors: Nobrega
authors: Ke-Li
authors: KL
authors: Han
authors: Qiang
authors: Q
authors: Cui
authors: Chuan
authors: C
authors: He
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D006801:Humans; D007700:Kinetics; D008322:Mammals / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012313:RNA; C046517:N(6)-hydroxymethyladenosine; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D000241:Adenosine
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