Structural insights into the regulation of Dnmt1 function. (A) Dnmt1 domain structure and interacting factors. Both the TS domain and the CXXC domain, plus adjacent linker, have been suggested to have an autoinhibitory function by interfering with substrate DNA binding. PBD, proliferating cell nuclear antigen (PCNA) binding domain; TS, targeting sequence; CXXC, zinc finger domain; BAH1/2, bromo-adjacent homology domain 1/2; TRD, target recognizing domain. (B) Structure of Dnmt1 solved by Takeshita et al. (1) (PDB ID code 3AV4). The single domains are color-coded as in A. (C) Superposition of Dnmt1 structures illustrating the expected sterical clash between the TS domain, CXXC domain plus adjacent linker, and DNA. Note that the structure from Takeshita et al. (1) starts with the TS domain (pink; TS domain in surface representation), whereas the shorter structure from Song et al. (12) starts with the CXXC domain and is solved in complex with unmethylated DNA (DNA in blue, CXXC domain/autoinhibitory linker in black, and remaining structure in cyan; PDB ID code 3PT6).