*4.3.3 TDG*

Thymine DNA Glycosylase (TDG) is a 46 kDa protein that is located in the nucleus and plasma membrane of the cell. Despite UNG, SMUG1 and TDG sharing less than 10% amino acid similarity they all have similar structures and are located on the same arm of chromosome 12; additionally, they all may have evolved from the same ancestral gene [76]. In contrast to UNG, TDG is highly expressed during G1 and G2-M phases of the cell cycle and not in S-phase, while UNG is highly expressed only in S-phase [77]. TDG is known to remove U:G and T:G mismatches (derived from deaminated 5-methylcytosine (5-mC)) from DNA, with better efficiency with U:G mismatches [78]; however, seems to overall have a very slow turnover rate. Additionally, TDG has higher affinity for U:G mismatches, but also has a very high affinity for abasic sites opposite Gs [79] and it has been reported that TDG SUMOylation helps dissociate it from abasic sites [80]. TDG is also able to remove 5-hmU, thymine glycol halogenated pyrimidines and εC (caused by lipid peroxidation) when they are paired with G. Unlike UNG and SMUG1, when TDG is knocked out of mice it is embryonically lethal [81]. Rather than associating the lethality with TDG's U-DNA glycosylase activity, it is thought this is due to disruption of TDG's association with promoters, transcription factors, transcriptional coactivators and DNA methyltransferase which impairs the epigenetic regulation of developmental genes [81, 82]. Furthermore, TDG has been reported to directly induce DNA demethylation by removing 5-formylC (5-fC) and 5-carboxyC (5-aC) (both derived from TET-mediated oxidation of 5-mC), which leads to BER and repair of the site a non-modified C [83, 84].
