Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A Methylation.
N6-methyladenosine (m6A) is the most abundant mRNA modification and is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of m6A methylation in mRNA metabolism has been well documented recently, regulation of the m6A machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as ... positive regulators of the m6A 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 m6A methyltransferase complex. Lack of METTL3/WTAP phosphorylation reduces decay of m6A-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 m6A methylation.
Mesh Terms:
Adenine, Animals, Carcinogenesis, Embryo, Mammalian, Endopeptidases, Extracellular Signal-Regulated MAP Kinases, Fibroblasts, Humans, Melanoma, Methylation, Methyltransferases, Mice, Mice, Knockout, Phosphorylation, Protein Stability, RNA Processing, Post-Transcriptional
Adenine, Animals, Carcinogenesis, Embryo, Mammalian, Endopeptidases, Extracellular Signal-Regulated MAP Kinases, Fibroblasts, Humans, Melanoma, Methylation, Methyltransferases, Mice, Mice, Knockout, Phosphorylation, Protein Stability, RNA Processing, Post-Transcriptional
Mol Cell
Date: Dec. 19, 2019
PubMed ID: 33217317
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