The DNA methyltransferase 3 (DNMT3) family of DNMT proteins perform intial methylation of cytosines to form 5-methylcytosine at CpG (cytosine-phosphate-guanine) sites on the DNA. Once methylation is established on DNA, DNMT1 protein is responsible for maintaining the CpG methylation pattern during chromosome replication. The DNMT3 family includes the two active members, DNMT3a and DNMT3b, and the regulatory factor DNMT3-like protein (DNMT3L). DNMT3L contains a cysteine-rich, DNMT3/ATRX homology or ATRX-DNMT3-DNMT3L (ADD) domain; however it lacks the proline-tryptophan-tryptophan-proline (PWWP) domain, required for non-specific DNA binding. The ADD domain of DNMT3L is responsible for specifically binding to unmethylated histone H3 lysine 4 (H3K4me0). DNMT3L also lacks the conserved residues in the C-terminal DNA MTase domain of DNMT3a and 3b that are required for activity. However, DNMT3L is required to stimulate the DNA methylation activity of DNMT3a and 3b through interactions with the catalytic domain of DNMT3a and 3b.
