Human m⁶A writers: Two subunits, 2 roles

Cellular RNAs with diverse chemical modifications have been observed, and N⁶-methyladenosine (m⁶A) is one of the most abundant internal modifications found on mRNA and non-coding RNAs, playing a vital role in diverse biologic processes. In humans, m⁶A modification is catalyzed by the METTL3-METTL14 methyltransferase complex, which is regulated by WTAP and another factor. Three groups have recently and independently reported the structure of this complex with or without cofactors. Here, we focus on the detailed mechanism of the m⁶A methyltransferase complex and the properties of each subunit. METTL3 is predominantly catalytic, with a function reminiscent of N⁶-adenine DNA methyltransferase systems, whereas METTL14 appears to be a pseudomethyltransferase that stabilizes METTL3 and contributes to target RNA recognition. The structural and biochemical characterization of the METTL3-METTL14 complex is a major step toward understanding the function of m⁶A modification and developing m⁶A-related therapies.