Base excision repair (BER) is essential for maintaining genetic integrity and for active DNA demethylation, a central element of epigenetic gene regulation. A key player in both processes is thymine DNA glycosylase (TDG), which excises modified forms of 5-methylcytosine (mC). Thus, TDG excises thymine from mutagenic G/T mispairs arising from deamination of mC (to T), and it removes 5-formylcytosine (fC) and 5-carboxylcytosine (caC), oxidized forms of mC generated by Tet enzymes. The glycosylase activity of TDG is essential for embryonic development, reflecting a key role in regulating gene expression via DNA demethylation. We have used structural, biochemical, and mutagenesis approaches to understand how TDG attains specificity for excising a select but diverse group of deaminated and/or oxidized forms of mC. We have also employed a novel TDG variant that can excise fC, but not caC, to study the mechanism by which TDG mediates active DNA demethylation in human cells.

Mechanism of Thymine DNA glycosylase in maintaining genetic and epigenetic integrity

245th National Meeting (2013)

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