DNA cytosine methylation that typically refers to 5-methylcytosine (5mC) is established through DNA methyltransferases (DNMTs) and is a crucial epigenetic marker. In addition to 5mC, variants of DNA methylation have recently been discovered in mammals, including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Although they are similar in structure to the 5mC, they are much less abundant. In mammals, the Ten-Eleven Translocation (TET) family protein of methylcytosine dioxygenases oxidizes 5mC to 5hmC, which is a relative stable modification. When cells divide, 5mC is passively diluted by DNA replication, but symmetric methylation is restored by the maintenance methyltransferase complex DNMT1/UHRF1. The 5hmC is also passively diluted as a function of cell division, which leads to DNA demethylation. DNA demethylation can also occur by further oxidation of 5hmC to 5fC and 5caC via TET proteins. Both 5fC and 5caC can be removed by thymine DNA glycosylase (TDG), resulting in replacement of unmodified cytosine by base excision repair. It is widely believed that these modifications represent a pathway for demethylation of active DNA, thereby reshaping the methylated DNA landscape established by DNMTs.
