Methylation at the 5-position of DNA cytosine on the vertebrate genomes is 
accomplished by the combined catalytic actions of three DNA methyltransferases 
(DNMTs), the de novo enzymes DNMT3A and DNMT3B and the maintenance enzyme DNMT1. 
Although several metabolic routes have been suggested for demethylation of the 
vertebrate DNA, whether active DNA demethylase(s) exist has remained elusive. 
Surprisingly, we have found that the mammalian DNMTs, and likely the vertebrates 
DNMTs in general, can also act as Ca(2+) ion- and redox state-dependent active 
DNA demethylases. This finding suggests new directions for reinvestigation of 
the structures and functions of these DNMTs, in particular their roles in Ca(2+) 
ion-dependent biological processes, including the genome-wide/local DNA 
demethylation during early embryogenesis, cell differentiation, neuronal 
activity-regulated gene expression, and carcinogenesis.