Maintenance of genomic methylation patterns is mediated primarily by DNA 
methyltransferase-1 (DNMT1). We have solved structures of mouse and human DNMT1 
composed of CXXC, tandem bromo-adjacent homology (BAH1/2), and methyltransferase 
domains bound to DNA-containing unmethylated CpG sites. The CXXC specifically 
binds to unmethylated CpG dinucleotide and positions the CXXC-BAH1 linker 
between the DNA and the active site of DNMT1, preventing de novo methylation. In 
addition, a loop projecting from BAH2 interacts with the target recognition 
domain (TRD) of the methyltransferase, stabilizing the TRD in a retracted 
position and preventing it from inserting into the DNA major groove. Our studies 
identify an autoinhibitory mechanism, in which unmethylated CpG dinucleotides 
are occluded from the active site to ensure that only hemimethylated CpG 
dinucleotides undergo methylation.