Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases mA Methylation.

N-methyladenosine (mA) is the most abundant mRNA modification and is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of mA methylation in mRNA metabolism has been well documented recently, regulation of the mA machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the mA deposition. We find that ERK phosphorylates METTL3 at S43/S50/S525 and WTAP at S306/S341, followed by deubiquitination by USP5, resulting in stabilization of the mA methyltransferase complex. Lack of METTL3/WTAP phosphorylation reduces decay of mA-labeled pluripotent factor transcripts and traps mouse embryonic stem cells in the pluripotent state. The same phosphorylation can also be found in ERK-activated human cancer cells and contribute to tumorigenesis. Our study reveals an unrecognized function of ERK in regulating mA methylation.