The maintenance methylation of hemimethylated CpG sites by the DNA 
methyltransferase Dnmt1 is the molecular basis of the inheritance of DNA 
methylation patterns. Based on structural data and kinetics obtained with a 
truncated form of Dnmt1, an autoinhibition model for the specificity of Dnmt1 
was proposed in which unmethylated DNA binds to Dnmt1's CXXC domain, which 
prevents its methylation. We have prepared CXXC domain variants that lost DNA 
binding. Corresponding full-length Dnmt1 variants did not display a reduction in 
specificity, indicating that the autoinhibition model does not apply in 
full-length Dnmt1. Furthermore, we show that the Dnmt1 M1235S variant, which 
carries an exchange in the catalytic domain of the enzyme, has a marked 
reduction in specificity, indicating that the recognition of the hemimethylated 
state of target sites resides within the catalytic domain.