In the past few years, active cytosine demethylation evolved from being considered highly controversial to becoming a recognized phenomenon whose molecular basis is being unraveled. In our work, we showed that either knockout or catalytic inactivation of the base excision repair enzyme Thymine DNA Glycosylase (TDG) leads to embryonic lethality in mice and altered DNA methylation patterns. TDG plays a dual role in promoting proper epigenetic states during development: TDG is necessary for recruiting p300 to retinoic acid-regulated promoters, acting as an important transcriptional co-activator and, at the same time, is involved in protection of CpG islands from hypermethylation, and active demethylation of tissue-specific, developmentally- and hormonally-regulated promoters and enhancers. This critical role of TDG is linked to its biochemical activity as it relates to the newly identified repertoire of modified cytosine bases in mammalian genomes. In fact, TDG interacts with the deaminase AID and has glycosylase activity on 5-hydroxymethyluracil, the deamination product of 5-hydroxymethylcytosine, which in turn originates from 5-methylcytosine oxidation by the TET oxidases; in addition, TDG exhibits glycosylase activity on 5-formylcytosine and 5-carboxylcytosine, two iterative oxidation products of 5-hydroxymethylcytosine. Thus, TDG could be involved in both deaminase-dependent and -independent pathways of active DNA demethylation by base excision repair. Implications of these findings for epigenetic deregulation in cancer will be discussed.

Active DNA demethylation by thymine DNA glycosylase

244th National Meeting (2012)

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