title: Reversible methylation of m6Amin the 5' cap controls mRNA stability.
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 m6Amwe 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 m6Amis selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m6Amrather than N6-methyladenosine (m6A), and reduces the stability of m6AmmRNAs. Together, these findings show that the methylation status of m6Amin the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Mauer
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Chemistry, IBMM UMR 5247, CNRS, Université de Montpellier ENSCM, UM Campus Triolet, Place E. Bataillon, 34095 Montpellier Cedex 05, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Blanjoie
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Xinfu
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Anya V
authors.initials: AV
authors.lastname: Grozhik
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Deepak P
authors.initials: DP
authors.lastname: Patil
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Bastian
authors.initials: B
authors.lastname: Linder
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Pickering
authors.affiliation: Department of Chemistry, IBMM UMR 5247, CNRS, Université de Montpellier ENSCM, UM Campus Triolet, Place E. Bataillon, 34095 Montpellier Cedex 05, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Vasseur
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.|HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College, Cornell University, New York, New York 10065, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Chemistry, IBMM UMR 5247, CNRS, Université de Montpellier ENSCM, UM Campus Triolet, Place E. Bataillon, 34095 Montpellier Cedex 05, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Debart
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Megerditch
authors.initials: M
authors.lastname: Kiledjian
authors.affiliation: Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
authors.forename: Samie R
authors.initials: SR
authors.lastname: Jaffrey
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism; D000818:Animals; D004722:Endoribonucleases / Q000378:metabolism; D044127:Epigenesis, Genetic; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D012315:RNA Caps / Q000737:chemistry* / Q000378:metabolism*; D020871:RNA Stability; D013379:Substrate Specificity; D024363:Transcription Initiation Site; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; D012315:RNA Caps; C030052:mRNA decapping enzymes; D006151:Guanosine; C016578:7-methylguanosine; C016395:N(6),O(2)-dimethyladenosine; C010223:N-methyladenosine; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D004722:Endoribonucleases; D000241:Adenosine