P53 is the most important protein that functions as a safeguard against tumor development. It is also the most frequently inactivated protein in human cancer. However, p53 functions with other proteins and has been shown to cooperate in cancer suppression with a number of proteins important for the signaling and repair of DNA damage. Recent studies identified RNF8 and RNF168 as essential factors for DNA damage signaling and repair. We have generated mice lacking either RNF8 or RNF168 and observed that they have elevated level of p53. These mice also carry increased level of chromosomal abberations, a hallmark of increased cancer risk. Interestingly, our data has already confirmed that RNF8 mice are highly predisposed for tumorigenesis. We will examine the effect of p53 inactivation on tumorigenesis of mice lacking either RNF8 or RNF168. We will also examine whether the expression of RNF8 and RNF168 is affected in human tumors and will evaluate the responses of human tumors deficient for RNF8 and RNF168 to radiation and chemotherapeutic drugs.