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Reversible methylation of m6Am in the 5′ cap controls mRNA stability

Author

Listed:
  • Jan Mauer

    (Weill Cornell Medicine, Cornell University)

  • Xiaobing Luo

    (Rutgers University)

  • Alexandre Blanjoie

    (IBMM UMR 5247, CNRS, Université de Montpellier ENSCM, UM Campus Triolet, Place E. Bataillon)

  • Xinfu Jiao

    (Rutgers University)

  • Anya V. Grozhik

    (Weill Cornell Medicine, Cornell University)

  • Deepak P. Patil

    (Weill Cornell Medicine, Cornell University)

  • Bastian Linder

    (Weill Cornell Medicine, Cornell University)

  • Brian F. Pickering

    (Weill Cornell Medicine, Cornell University)

  • Jean-Jacques Vasseur

    (IBMM UMR 5247, CNRS, Université de Montpellier ENSCM, UM Campus Triolet, Place E. Bataillon)

  • Qiuying Chen

    (Weill Cornell Medicine, Cornell University)

  • Steven S. Gross

    (Weill Cornell Medicine, Cornell University)

  • Olivier Elemento

    (Weill Cornell Medicine, Cornell University
    HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College, Cornell University)

  • Françoise Debart

    (IBMM UMR 5247, CNRS, Université de Montpellier ENSCM, UM Campus Triolet, Place E. Bataillon)

  • Megerditch Kiledjian

    (Rutgers University)

  • Samie R. Jaffrey

    (Weill Cornell Medicine, Cornell University)

Abstract

Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5′ end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N6,2′-O-dimethyladenosine (m6Am), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of m6Am we find that m6Am-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of m6Am-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that m6Am is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m6Am rather than N6-methyladenosine (m6A), and reduces the stability of m6Am mRNAs. Together, these findings show that the methylation status of m6Am in the 5′ cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.

Suggested Citation

  • Jan Mauer & Xiaobing Luo & Alexandre Blanjoie & Xinfu Jiao & Anya V. Grozhik & Deepak P. Patil & Bastian Linder & Brian F. Pickering & Jean-Jacques Vasseur & Qiuying Chen & Steven S. Gross & Olivier E, 2017. "Reversible methylation of m6Am in the 5′ cap controls mRNA stability," Nature, Nature, vol. 541(7637), pages 371-375, January.
    • Handle: RePEc:nat:nature:v:541:y:2017:i:7637:d:10.1038_nature21022
    DOI: 10.1038/nature21022
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    Cited by:

    1. Moshe Shay Ben-Haim & Yishay Pinto & Sharon Moshitch-Moshkovitz & Vera Hershkovitz & Nitzan Kol & Tammy Diamant-Levi & Michal Schnaider Beeri & Ninette Amariglio & Haim Y. Cohen & Gideon Rechavi, 2021. "Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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