Tet proteins: on track towards DNA demethylation?

Abstract Dynamic DNA methylation is a prerequisite for many developmental processes and maintenance of cellular integrity. In mammals however, mechanisms of active DNA demethylation have for long been elusive. The discovery of the ten-eleven translocation (Tet) family of enzymes that oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) or 5-carboxylcytosine (5caC) provided new means by which DNA methylation could actively be reversed. This review focuses on the possible mechanisms of DNA demethylation via Tet proteins and their metabolites 5hmC, 5fC and 5caC. Additionally, it discusses the roles of the three Tet protein family members Tet1, Tet2 and Tet3 as developmental regulators, probably in part independent of their enzymatic activity. By contrast, recent evidence suggests a function of 5hmC as an epigenetic mark on its own, going beyond the expectation of only acting as an intermediate in an active DNA demethylation pathway.