Reversible methylation of mA in the 5' cap controls mRNA stability.

TitleReversible methylation of mA in the 5' cap controls mRNA stability.
Publication TypeJournal Article
Year of Publication2017
AuthorsMauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF, Vasseur J-J, Chen Q, Gross SS, Elemento O, Debart F, Kiledjian M, Jaffrey SR
JournalNature
Volume541
Issue7637
Pagination371-375
Date Published2017 01 19
ISSN1476-4687
KeywordsAdenosine, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Animals, Endoribonucleases, Epigenesis, Genetic, Guanosine, Half-Life, HEK293 Cells, Humans, Male, Methylation, Mice, MicroRNAs, RNA Caps, RNA Stability, Substrate Specificity, Transcription Initiation Site, Transcriptome
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, N,2'-O-dimethyladenosine (mA), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of mA we find that mA-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of mA-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that mA is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates mA rather than N-methyladenosine (mA), and reduces the stability of mA mRNAs. Together, these findings show that the methylation status of mA in the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.

DOI10.1038/nature21022
Alternate JournalNature
PubMed ID28002401
PubMed Central IDPMC5513158
Grant ListR37 HL087062 / HL / NHLBI NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States
R01 GM067005 / GM / NIGMS NIH HHS / United States
R01 CA186702 / CA / NCI NIH HHS / United States
R01 DA037150 / DA / NIDA NIH HHS / United States
P01 HD067244 / HD / NICHD NIH HHS / United States
R01 DA037755 / DA / NIDA NIH HHS / United States
T32 HD060600 / HD / NICHD NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States