The major focus of this project is to understand how cells monitor and repair DNA damage. Defects in either the surveillance or repair of damaged DNA can lead to chromosomal instability and cancer. For example, inherited disorders affecting cellular responses to DNA damage, such as Nijmegen breakage syndrome and ataxia telangiectasia are characterized by increased susceptibility to lymphoid cancer, extreme radiation sensitivity and immunodeficiency. We are generating knockout and transgenic mouse models that have specific defects in DNA double strand break (DSB) repair. Recently, we characterized mice that were defective in non-homologous end joining, the major pathway for repairing DSBs in mammalian cells. We found that these mice displayed premature aging, a defect in cellular proliferation, a complete block in lymphocyte development and extreme radiation sensitivity. Surprisingly, however, the mice were not prone to cancer. However, a further inactivation of the p53 tumor suppressor gene markedly increased cancer susceptibility, such that these "double knockout" mice invariably succumbed to B-cell lymphomas that resembled human Burkitt's lymphoma. Other mouse models for DNA double strand break repair are being generating including animals that lack the Nijmegen breakage sydrome protein.

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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Lee, Baeck-Seung; Gapud, Eric J; Zhang, Shichuan et al. (2013) Functional intersection of ATM and DNA-dependent protein kinase catalytic subunit in coding end joining during V(D)J recombination. Mol Cell Biol 33:3568-79
Bunting, Samuel F; Nussenzweig, Andre (2013) End-joining, translocations and cancer. Nat Rev Cancer 13:443-54
Callen, Elsa; Jankovic, Mila; Wong, Nancy et al. (2009) Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes. Mol Cell 34:285-97
Difilippantonio, Simone; Gapud, Eric; Wong, Nancy et al. (2008) 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456:529-33