Why does the m6A writer complex require so many proteins?
Fig 1
m6A methylation requires a multi-protein writer complex.
The m6A writer complex is a multi-component assembly that deposits N6-methyladenosine (m6A) on mRNA in a transcriptome-wide yet site-selective manner. In the writer complex, only METTL3 contains the catalytic domain, but optimal methylation requires additional non-catalytic auxiliary proteins. Unlike other RNA modifications that are catalyzed by single enzymes, m6A methylation requires a multi-protein complex. By contrast, NSUN2 (a cytosine-5 RNA methyltransferase) and pseudouridine synthase (PUS) enzymes typically function as single-protein modifiers that act on defined RNA substrates. NSUN2 catalyzes 5-methylcytosine (m5C) deposition primarily on tRNAs, but also on vault RNAs, 7SK RNA and some mRNAs, where it regulates the RNA’s stability and translation. PUS enzymes convert uridine to pseudouridine (Ψ) on tRNAs, rRNAs, snRNAs and a subset of mRNAs in a site-specific manner. The necessity for a multi-protein complex for m6A deposition and the roles of each writer complex component remains a mystery. Created in BioRender. Jaffrey, S. (2025) https://BioRender.com/hffsuxx.