Figure 1.
Deposition, removal, and recognition of m6A modification. The m6A modification is deposited by “writers” that function as a complex or as a single protein (METTL16). The MTC consists of 3 key components (METTL3, METTL14, and WTAP) and several auxiliary subunits (including RBM15/15B, KIAA1429, and ZC3H13). Two m6A demethylases, FTO and ALKBH5, serve as “erasers” and can reverse m6A to A in an α-ketoglutarate (α-KG)-dependent way. Notably, R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenase, is reported to competitively suppress the demethylase activity of FTO as a result of its similar structure to α-KG. The broad biological functions of m6A are mediated by “readers” that are able to recognize the methyl group or m6A-induced structural changes (“the m6A switch”) to regulate gene expression of downstream targets. Currently known readers include the YTH family (YTHDF1/2/3 and YTHDC1/2), the IGF2BP family (IGF2BP1/2/3), and other proteins (eg, hnRNPA2B1, hnRNPC, and hnRNPG) that recognize m6A switches.