Hereditary deficiencies in DNA damage surveillance and signaling are invariably associated with cancer predisposition, radiation sensitivity, immunodeficiency, gonadal abnormalities, and tissue degeneration. These so-called chromosomal instability disorders include ataxia telangiectasia (AT), ataxia-like disorder (ATLD) and Nijmegen breakage syndrome (NBS). AT is caused by null mutations in the protein kinase ATM, whereas hypomorphic mutations in Mre11 and Nbs1 underlie ATLD and NBS respectively. Mre11, Rad50 and Nbs1 form a complex (MRN) that is required for the activation and recruitment of ATM to DNA breaks, which may explain the phenotypic overlap between NBS, ATLD and AT. The objective of this project is to delineate the critical regions in ATM and Nbs1 that regulate tumor suppression, immune system function and meiotic recombination. To accomplish this, we will generate humanized mouse models of AT and NBS by reconstituting ATM-/- and Nbs1-/- mice with bacterial artificial chromosomes (BACs) that carry mutations in critical domains of human ATM and Nbs1. We will explore the in vivo consequences of specific amino acid changes that individually abrogate ATM activity, ATM-dependent Nbs1 phosphorylation, and ATM recruitment to DNA breaks. The analysis of these humanized transgenic mice will provide mechanistic insight into the central question of how the DNA damage signal is transmitted to and activates ATM.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Salewsky, Bastian; Hildebrand, Gabriele; Rothe, Susanne et al. (2016) Directed Alternative Splicing in Nijmegen Breakage Syndrome: Proof of Principle Concerning Its Therapeutical Application. Mol Ther 24:117-24
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