In the DNA?of higher eukaryotes,hydrolytic deamination of 5-methylcytosine to thymine leads to the formation of G/T?mismatches. G/T?mismatch specific Thymine DNA?Glycosylase (TDG) is a nuclear protein?which corrects G/T?mismatches to G/C pairs by hydrolyzing the carbon nitrogen bond between the sugar phosphate backbone of the DNA?and the mispaired thymine. TDG?also corrects a subset of G/U mispairs inefficiently removed by the more abundant uracil glycosylases. Retinoic acid?receptors interact physically and functionally with TDG,enhancing the ability of the retinoid?X receptor and the retinoid?X?receptor/retinoid acid receptor complex to bind to their?response elements. TDG?interacts with,and is covalently modified by,the ubiquitin-like proteins SUMO-1 and SUMO-2/3,resulting in?a reduction of the DNA?substrate and AP site binding affinity of TDG. This sumoylation is associated with a significant increase in enzymatic turnover in reactions with a G/U substrate and the loss of G/T?processing activity.