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

Author

Listed:
  • Ye Fu

    (The University of Chicago)

  • Guifang Jia

    (The University of Chicago)

  • Xueqin Pang

    (University of Wisconsin
    State Key Laboratory of Molecular Reaction Dynamics and Center for Theoretical and Computational Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Richard N. Wang

    (The University of Chicago)

  • Xiao Wang

    (The University of Chicago)

  • Charles J. Li

    (The University of Chicago)

  • Scott Smemo

    (The University of Chicago)

  • Qing Dai

    (The University of Chicago)

  • Kathleen A. Bailey

    (The University of Chicago)

  • Marcelo A. Nobrega

    (The University of Chicago)

  • Ke-Li Han

    (State Key Laboratory of Molecular Reaction Dynamics and Center for Theoretical and Computational Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Qiang Cui

    (University of Wisconsin)

  • Chuan He

    (The University of Chicago)

Abstract

N6-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, N6-hydroxymethyladenosine (hm6A) and N6-formyladenosine (f6A), in mammalian messenger RNA. We show that FeII- and α-ketoglutarate-dependent fat mass and obesity-associated (FTO) protein oxidize N6-methyladenosine to generate N6-hydroxymethyladenosine as an intermediate modification, and N6-formyladenosine as a further oxidized product. N6-hydroxymethyladenosine and N6-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 N6-methyladenosine in messenger RNA, formed through oxidative RNA demethylation, may dynamically modulate RNA–protein interactions to affect gene expression regulation.

Suggested Citation

  • Ye Fu & Guifang Jia & Xueqin Pang & Richard N. Wang & Xiao Wang & Charles J. Li & Scott Smemo & Qing Dai & Kathleen A. Bailey & Marcelo A. Nobrega & Ke-Li Han & Qiang Cui & Chuan He, 2013. "FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2822
    DOI: 10.1038/ncomms2822
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