DNA methylation is an important epigenetic modification that is essential for various developmental processes. There are two kinds of DNA methylation enzyme, DNMT3a/3b and DNMT1. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive form of DNMT3 enzymes. Here, we report the structures of DNMT3a.
Firstly, we determine the crystal structures of DNMT3A–DNMT3L (auto-inhibitory form) and DNMT3A–DNMT3L-H3 (active form) complexes at 3.82 and 2.90 A resolution.
Next, we found the interaction between the ADD domain and the catalytic domain (CD). The intramolecular interaction was verified in the in vitro glutathione S- transferase (GST) pull-down assays, in which ADD–linker bound to the CD domain. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity.
Finally, on the point of biology role, the ADD domain inhibits the activity of the CD domain by decreasing its DNA-binding affinity. This inhibition is restored by fusion of the histone H3 tail at the N terminus of ADD–CD.
This work shows the connection between DNA methylation and histone modifications, and sheds new light on regulation of the establishment of DNA methylation. The structures may also provide a basis for the design of specific regulators for potential therapeutic applications.