Demethylation of Non-CpG Sites in DNA Is Initiated by TET2 5-Methylcytosine Dioxygenase

In the mammalian genome, cytosine methylation predominantly occurs at CpG sites. addition, a number of recent studies have uncovered extensive C5 (5mC) non-CpG (5mCpH, where H = A/C/T) Little is known about enzyme responsible for active demethylation 5mCpH Using very sensitive and quantitative LC–MS/MS method, we demonstrate that human TET2, an iron (II)- 2OG-dependent dioxygenase, which frequently mutated gene in several myeloid malignancies, as well other types cancers, can oxidize sites double-stranded DNA vitro. Similar to oxidation 5mCpG, 5mC CpH produces 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxycytosine (5caC) bases DNA. After most preferred substrate, TET2 prefers 5mCpC followed by 5mCpA then 5mCpT. Since TDG/BER pathway deformylation or decarboxylation 5fC 5caC, respectively, convert 5fCpH 5caCpH unmodified base DNA, our results suggest novel initiated dioxygenase.