The MRN complex in Lymphocyte Development and Genome Stability

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Abstract Cellular responses to DNA double strand breaks require rapid communication between specialized DNA damage recognition complexes and the core cell cycle machinery, but this important relationship is poorly understood. Mre11, a core component of the DNA damage recognition machinery that is mutated in ataxia-telangiectasia like disorders (ATLD), has been shown to interact with cyclin dependent kinase 2 (CDK2), a core component of the cell cycle machinery. In this proposal we will test the overarching hypothesis that Mre11 interacts with and controls CDK2 to provide a rapid switch between the normal cell cycle and the DNA damage response. We will determine roles that Mre11-CDK2 interaction plays in diverse biological contexts such as specialized DNA recombination in lymphocyte development, and S phase checkpoint responses more generally. The studies proposed herein take advantage of previously constructed murine systems, along with new mouse lines that model human ataxia telangiectasia-like disorder. Collectively, the proposed studies will significantly contribute to our understanding of cellular responses to DNA damage and their associated diseases.