PRMT1 methylates METTL14 to modulate its oncogenic function

N6-methyladenosine (m6A), the most abundant mRNA modification in mammalian cells, is responsible for mRNA stability and alternative splicing. The METTL3-METTL14-WTAP complex is the only methyltransferase for the m6A modification. Thus, regulation of its enzymatic activity is critical for the homeostasis of mRNA m6A levels in cells. However, relatively little is known about the upstream regulation of the METTL3-METTL14-WTAP complex, especially at the post-translational modification level. The C-terminal RGG repeats of METTL14 are critical for RNA binding. Therefore, modifications on these residues may play a regulatory role in its function. Arginine methylation is a post-translational modification catalyzed by protein arginine methyltransferases (PRMTs), among which PRMT1 preferentially methylates protein substrates with an arginine/glycine-rich motif. In addition, PRMT1 functions as a key regulator of mRNA alternative splicing, which is associated with m6A modification. To this end, we report that PRMT1 promotes the asymmetric methylation of two major arginine residues at the C-terminus of METTL14, and the reader protein SPF30 recognizes this modification. Functionally, PRMT1-mediated arginine methylation on METTL14 is likely essential for its function in catalyzing the m6A modification. Moreover, arginine methylation of METTL14 promotes cell proliferation that is antagonized by the PRMT1 inhibitor MS023. These results indicate that PRMT1 likely regulates m6A modification and promotes tumorigenesis through arginine methylation at the C-terminus of METTL14.