This proposal addresses the mechanistic and genetic basis for the Mre11 complex's role in the suppression of malignancy. Using yeast and mouse models, it focuses primarily on DNA repair and DNA damage signaling alterations imparted by alleles of RAD50 that affect the coiled-coil and hook domains of the protein. We the mutants derived in this effort are separations of function that will allow us to define the role of particular Mre11 complex-dependent mechanisms meiosis, DNA repair, and the suppression of tumorigenesis. The governing hypothesis of this proposal is that the Mre11 complex suppresses tumorigenesis through its affect on chromosome integrity in addition to its influence on DNA damage signaling. We propose a series of experiments in mice and yeast to address the cancer preventing functions of the complex. First, we investigate the importance of recruitment of DNA repair factors by the Mre11 complex. Second, we examine the effect of mutations within the Rad50 hook domain on NHEJ and HR. Third, we integrate the knowledge gained in the first two Aims for the analysis of new mouse models for Rad50 dysfunction that selectively impair NHEJ. Genetic interactions with these mice and mice mutants in p53, ATM and PTEN will be examined to test the hypothesis that chromosome instability in Rad50 mutants will increase the penetrance of mutations affecting these tumor suppressor proteins and predispose to cancer.
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 increase 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.
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