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.
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.

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