Fig. 7.

Schematic model of tandem “HxH” methylation by METTL9. Methylation of tandem “HxH” repeats by METTL9 can occur in two modes. In the stochastic mode, METTL9 recognizes the “HxH” motif and methylate the H_i residue in a random manner since methylated H_i impairs successive H_i+2 methylation, which leads to products with scattered methylation pattern. In the consecutive mode, recognition of an initial “HxH” motif and subsequent H_i methylation shall promote sequential “C-to-N” methylation, as release of methylated H_i product can be well coupled with relocation of the adjacent H_i-2 residue into the H_i pocket for next round of methylation. Our enzymatic assays suggested that consecutive “C-to-N” methylation exists as the major mode as indicated by big red arrows.