Figure 2.

Functional roles of m⁶A modification on mRNA expression. Most of m⁶A’s effects on mRNA metabolism are mediated by reader proteins whose binding can be directly or indirectly affected by m⁶A. In the nucleus, the direct readers are YTHDC1 and HNRNPA2, which stimulate splicing and microRNA processing, respectively. YTHDC1 also stimulates mRNA export. The splicing regulator HNRNPC (heterogeneous nuclear ribonucleoprotein) is an indirect reader whose binding is favored by structural rearrangement induced by m⁶A modification. In the cytoplasm, mRNA translation is stimulated by the direct reader eIF3, ABCF1 (ATP binding cassette subfamily F member 1), YTHDF1, YTHDF3 and YTHDC2, while it is inhibited by the indirect reader FMR1. mRNA decay is increased by the direct readers YTHDF2, YTHDF3 and YTHDC2, while it is inhibited by the direct readers IGF2BPs (insulin-like growth factor 2 mRNA-binding protein) and the m⁶A-repelled proteins ELAVL1 (ELAV like RNA binding protein 1) and G3BPs (G3BP stress granule assembly factor).