Base excision repair (BER) activity is modulated in response to several stimuli by altering the expression of its pathway enzymes. Iododeoxyuridine (IUdR) generated mispairs form a substrate for DNA glycosylases-the initiator molecules of BER activity. Our lab has previously reported the involvement of MED1 in repairing IUdR:G mispairs under in vitro conditions. These mispairs were also found to be the substrates for strong enzymatic activity of thymidine DNA glycosylase (TDG). Under in vivo conditions, differential expression of these glycosylases may play a decisive role in the outcome of BER mediated repair process. In the present study, we are exploring a link between the generation of IUdR mispairs and the expression levels of the DNA glycosylases. We observed modulation of expression levels of MED1 in response to the treatment with IUdR. A time course study suggested increase of 66kDa MED1 molecular levels when human colon cancer cell lines were treated with 10μM IUdR. As evident from the flow cytometric analysis of asynchronized cell lines treated with same concentrations of IUdR, there was no significant change in cell cycle pattern until after 24 hrs of treatment. Similar modulation of MED1 expression levels was observed in response to ionizing radiation. We are further studying the alteration in TDG expression in response to IUdR and its possible link with the changes observed in levels of MED1. This study would eventually aid our endeavors to develop an integrated model of BER as operative on IUdR generated mispairs.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA