Figure 4. Direct and indirect effects of m⁶A modifications on reader protein binding.

Panels (A, B) show indirect m⁶A readers, whereas panels (C, D, E) show direct m⁶A readers or “anti-readers.” (A) “m⁶A-switch” mechanism 1: methylation of DRACH motifs by the m⁶A writer complex within RNA hairpins leads to the release of U-rich stretches, which can then be bound by RNA-binding protein hnRNP-C (Liu et al, 2015). (B) “m⁶A-switch” mechanism 2: Methylation of DRACH motifs by the m⁶A writer complex within RNA hairpins leads to the release of the DRACH motif from the RNA structure, which allows RNA-binding protein hnRNP-G to bind the single-stranded AGRAC motifs (R = A/G) with its low-complexity domain (Liu et al, 2017). The RRM domain of hnRNP-G can bind CC(A/C)-rich sequences independent of the m⁶A modification (Heinrich et al, 2009). (C) m⁶A modifications by the m⁶A writer complex create a new binding epitope for m⁶A reader proteins such as YTHDC1-2 and YTHDF1-3. (D) m⁶A marks within exons in pre-mRNA can be bound by m⁶A reader YTHDC-1 (orange), which recruits splicing factor SRSF3 (purple) that promotes exon inclusion and prevents binding of splicing factor SRSF10 (brown), which would promote exon skipping in the absence of the m⁶A mark. (E) m⁶A modifications by the m⁶A writer complex can also disrupt protein binding interfaces. The affected class of proteins is termed m⁶A “anti-readers.”