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

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 Elemento, Françoise Debart, Megerditch Kiledjian and Samie R. Jaffrey ()
Additional contact information
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
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

Nature, 2017, vol. 541, issue 7637, 371-375

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21022

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