This proposal is based on the novel finding that in addition to activating downstream components of the DNA damage response (DDR), the Mre11 complex-ATM arm of the DDR is required to activate a p53-dependent epigenetic program in response to oncogene activation. This pathway appears to parallel that governed by Ink4a-p19Arf. We will carry out quantitative analysis of the abundance and location of chromatin marks arising in response to the activation of neuT and c-myc, and assess changes in the expression of chromatin modifying enzymes in epithelial cells. To determine whether these responses are shared by hematopoietic cells, we will examine the same endpoints as well as the onset and progression of malignancy in p53-/- and Mre11ATLD1/ATLD1 bone marrow following introduction of c-myc or the Nup98-Hox9a cDNA. Finally, having defined these features of the p53-dependent epigenetic response to oncogene, we will identify enzymes that mediate this response and test the hypothesis that this p53-dependent function which requires DDR signaling is tumor suppressive. Collectively, the experiments proposed will illuminate a previously undescribed connection between p53 and the upstream components of the DDR that effects a barrier to oncogene-driven carcinogenesis. Therefore, this proposal is highly significant with the potential to provide novel mechanistic insight regarding tumor suppression by p53.