DNA demethylation dynamics

Abstract

The discovery of cytosine hydroxymethylation (5hmC) suggested a simple means of demethylating DNA and activating genes. Further experiments, however, unearthed an unexpectedly complex process, entailing both passive and active mechanisms of DNA demethylation by the ten-eleven translocation (TET) and AID/APOBEC families of enzymes. The consensus emerging from these studies is that removal of cytosine methylation in mammalian cells can occur by DNA repair. These reports highlight that in certain contexts, DNA methylation is not fixed but dynamic, requiring continuous regulation.

Figure 1. DNA Demethylation Pathways

Passive DNA demethylation has long been known to occur by a reduction in activity or absence of DNA methyl transferases (DNMTs) (black). DNMT3A and 3B are responsible for de novo DNA methylation whereas DNMT1 maintains DNA methylation patterns through successive rounds of cell division. Recently, three enzyme families have been implicated in active DNA demethylation via DNA repair. First, (1) 5-methylcytosine (5mC) can be hydroxylated by the ten-eleven translocation (TET) family of enzymes (blue), to form 5-hydroxymethylcytosine (5hmC) or further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). (2) 5mC (or 5hmC) can be deaminated by the AID/APOBEC family members (purple) to form 5-methyluracil (5mU) or 5-hydroxymethyluracil (5hmU). (3) Replacement of these intermediates (i.e., 5mU, 5hmU or 5caC) is initiated by the UDG family of base excision repair (BER) glycosylases (green) like TDG or SMUG1, culminating in cytosine replacement and DNA demethylation.