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The DNMT1 replication foci targeting sequence (RFTS) domain regulates DNMT1 enzymatic activity through an auto-inhibitory mechanism. (A) Crystal structure of human DNMT1 (aa: 351-1600; PDB: 4WXX) in free form [23]. (B) Crystal structure of mouse DNMT1 (aa:731-1602; PDB: 4DA4) bound by hemimethylated CpG DNA [31]. (C) Superimposition of structures in (A) and (B) revealed that the RFTS domain occupies DNMT1’s catalytic pocket and prevents substrate DNA binding.
