This renewal application exploits mouse models previously developed under the auspices of this grant to test the hypothesis that Mre11 complex-dependent DNA damage responses mitigate the oncogenic potential of oxidative and oncogene induced genotoxic stress. We focus on tumorigenic processes in mammary epithelium with as an exemplar of the general role of the DDR. In addition, we will test the hypothesis that DNA lesions imparted by oxidative damage pose a significant barrier to DSB repair, and that the enzymes involved in the processing of oxidative lesions such as those caused by ionizing radiation and radiomimetic compounds enhance the efficiency of both HR and NHEJ. For this issue, yeast and mouse models have been established. Finally, we have established novel mutant mice in which the ATM- independent functions of the Mre11 complex in the response to ionizing radiation and DNA replication stress can be assessed. Given the importance of the DDR in tumor suppression, meiosis, and development of the immune system, the research program proposed herein is highly significant with the potential to illuminate the functional impact of the Mre11 complex on multiple aspects of the DDR network. PUBLIC HEALTH RELEVANCE: Genome instability is a hallmark of cancer, and defects in the DNA damage response, which is required for the maintenance of genome stability are associated with cancer as well as human syndromes associated with reproductive, developmental and neurological defects. We address the functions of a central DNA damage response component, the Mre11 complex. This complex has been implicated in human chromosome instability syndromes associated with increased risk of malignancy, and has also found to be defective in sporadic cancers. The experiments described in this application examine the Mre11 complex and have the potential to provide insights regarding the mechanisms underlying cancer predisposition, as well as those that may present suitable targets for interdiction in therapeutic settings.