This request for a five year extension of the MERIT award continues to exploit mouse models previously developed under the auspices of this grant. Having demonstrated that Mre11 complex-dependent DNA damage responses mitigate the oncogenic potential of oxidative and oncogene induced genotoxic stress, we will focus on the type(s) of DNA alerations that ensue from oncogene activation. Also based on findings obtained since the last review, we will examine genetic interactions between the Mre11 complex and Brca1 and lnk4a-p19Arf. We will extend our analysis of DNA repair at by examining the interplay of the Ku heterodimer and the Mre11 complex at DNA double strand breaks ends, testing the hypothesis 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 continue our focus on the mechanisms of DNA damage signaling and ATM activation through the analysis of NBS1 mutants in which the Mre11 interaction interface is altered. These mice, Nbs1 mid mice, are unique in several respects and provide novel context in which mechanisms of DNA damage signaling can be illuminated. Complementing this effort, we will also define the minimal Nbs1 to test the hypothesis that modulation of the Mre11 dimer interface is the the critical function of Nbs1, and that ATM activation is at least partially mediated by protein domains on Mre11. Given the importance of the Mre11 complex 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 DNA damage response network.
We address the functions of a central DNA damage response component, the Mre11 complex. This complex has been implicated in human 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.
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