Figure 2.

Mechanisms of DNA demethylation. (a) Passive demethylation. This process occurs during replication, wherein one or more limiting factors (i.e., compromised DNMT function, absence of SAM) prevents methylation maintenance and results in the subsequent loss of 5mC residues. (b) Active demethylation. The figure shows TET enzymes (TET1, TET2, or TET3) (teal) catalyzing stepwise oxidation of 5mC, which is first converted into 5-hydoxymethylcytosine (5hmC), further oxidized into 5-formylcytosine (5fC), and finally converted into 5-carbocylcytosine (5caC). 5fC and 5caC intermediates can be recognized and removed by thymine DNA glycosylase (TDG) (violet). They are then replaced with an unmethylated cytosine nucleotide to complete the base excision repair (BER) process (figure from ref).⁵⁷