Reversible methylation of m6Am in the 5′ cap controls mRNA stability
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- 21 December 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 541 (7637), 371-375
- https://doi.org/10.1038/nature21022
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.Keywords
This publication has 59 references indexed in Scilit:
- Fasting Induced Cytoplasmic Fto expression in Some Neurons of Rat HypothalamusPLOS ONE, 2013
- ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse FertilityMolecular Cell, 2013
- The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragmentsNature Protocols, 2012
- Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop CodonsCell, 2012
- N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTONature Chemical Biology, 2011
- 2′-O methylation of the viral mRNA cap evades host restriction by IFIT family membersNature, 2010
- Mammalian microRNAs predominantly act to decrease target mRNA levelsNature, 2010
- Loss-of-Function Mutation in the Dioxygenase-Encoding FTO Gene Causes Severe Growth Retardation and Multiple MalformationsAmerican Journal of Human Genetics, 2009
- Let Me Count the Ways: Mechanisms of Gene Regulation by miRNAs and siRNAsMolecular Cell, 2008
- MicroRNA Targeting Specificity in Mammals: Determinants beyond Seed PairingMolecular Cell, 2007