FIGURE 1.

Cytosine methylation and oxidation cycle. In mammals, DNA methyltransferases (DNMTs) are responsible for the addition of a methyl group to the C5 position of cytosines to form 5-methylcytosines (5 mC). DNMT3A and DNMT3B drive de novo methylation during development, while DNMT1 is involved in maintaining DNA methylation by copying methylation patterns onto the newly replicated DNA strand. DNA methylation can be reversed in a passive way through replication-dependent dilution in absence of DNMT1. DNA demethylation can also occur actively, through Ten eleven translocation (TET) proteins that oxidize successively 5 mC into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5 fC) and 5-carboxylcytosine (5caC) and the replacement of the oxidized bases 5 fC and 5caC by an unmodified cytosine through thymine DNA glycosylase (TDG)-mediated abasic site (AP) formation and base excision repair (BER).