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Description

Four types of cytosine modifications have been identified in mammalian DNA, namely 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). While 5mC, 5hmC, and 5fC occur in embryonic stem (ES) cells and many cell types in all the major organs (e.g. brain, heart, lung and kidney), 5caC has only been detected in a few cell types at a 10 times lower level than 5fC. The sequential oxidation of 5mC to 5hmC, 5fC, and 5caC catalyzed by the ten-eleven translocation (TET) enzymes has been proposed as a potential route for the demethylation of 5mC back to cytosine (C). Thymine DNA glycosylase (TDG), for example, can excise 5fC and 5caC from DNA as part of the base excision repair (BER) pathway to restore the C-nucleotide. Emerging evidences suggest that the different modifications may be selectively recognized by various proteins, and methyl-CpG-binding protein 2 (MeCP2) binding to 5hmC has been proposed as a means of epigenetic regulation in neurons. The conversion of 5hmC to 5fC, in turn, induces an enhanced binding of DNA-repair-associated proteins to 5fC, which has been proposed as a signal for DNA demethylation.