Thymine-DNA glycosylase (TDG). a DNA repair enzyme specific for G/T mismatches, plays a role in the regulation Of gene expression through its physical interaction with transcription factors. Here, we show that TDG functionally associates with members of the p53 tumor suppressor family and directly modulates their activity. Yeast two-hybrid analysis indicated a physical interaction between a region including the oligomerization domain (CD) of p73 alpha (residues 345-380) or p53 (residues 319-360) and residues 123-346 of TDG, which localizes in the G/T glycosylase catalytic domain (residues 123-372). This interaction was also detected in vitro and in vivo by GST pull-down and immunoprecipitation assays, respectively. TDG over-expression promoted the p73- and p53-mediated transcriptional activation of the p21Waf1 promoter in a dose-dependent manner. Further, TDG enhanced the p53 or p73 alpha-induced growth repression. These observations suggest that TDG modulates the biological function of p53 and other members of the p53 family as a transcriptional coactivator. (C) 2008 Elsevier Inc. All rights reserved.