Title | Reversible methylation of mA in the 5' cap controls mRNA stability. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Mauer 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 |
Journal | Nature |
Volume | 541 |
Issue | 7637 |
Pagination | 371-375 |
Date Published | 2017 01 19 |
ISSN | 1476-4687 |
Keywords | Adenosine, 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. |
DOI | 10.1038/nature21022 |
Alternate Journal | Nature |
PubMed ID | 28002401 |
PubMed Central ID | PMC5513158 |
Grant List | R37 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 |