Fig. 1

Schematic diagram of DOT1L. a Schematic diagram illustrating the domain structures of human DOT1L. DOT1L, which has more than 1530 amino acids, contains an N-terminal histone methyltransferase domain (gray) (residues 1–332) and a large C-terminal region of unknown functions. hDOT1L is predicted to contain 4 tandem coiled-coil (CC) domains (aa 419–670), and the CC1–CC3 domains are involved in AF10 binding. DOT1L has 3 separate AF9 binding sites as follows: site 1 (aa 628–653), site 2 (aa 863–877), and site 3 (aa 878–900). b Schematic diagram of the catalytic domain of human DOT1L. The sites of DOT1L interacting with the acidic patch, histone H2A, histone H2B, histone H4, and ubiquitin are presented. c Secondary structure plot for DOT1L 1nw3-PDBsum entry 1nw3-Chain A (328 residues). d Structure of the catalytic domain of human DOT1L (PDB: 1NW3). e Schematic diagram of DOT1L. DOT1L exists in a large macromolecular complex known as DotCom, which includes fusion partners such as ENL, AF9, AF17, and AF10, as well as the known Wnt pathway modifiers TRRAP, Skp1, and β-catenin. DOT1L is recruited to RNA Pol II through its associated protein network, which is not limited to the proteins of the DotCom complex, DOT1L-mediated H3K79 methylation and the subsequent activation of the target genes, resulting in leukemic transformation. f DOT1L mechanism of action. DOT1L transfers the S-methyl group of (S)-adenosyl-l-methionine (SAM) to the amino group of H3K79, producing a methylated substrate and (S)-adenosyl-l-homocysteine (SAH)