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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010283-16
Application #
8763062
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2013
Total Cost
$1,148,001
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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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Ira, Grzegorz; Nussenzweig, André (2014) A new Riff: Rif1 eats its cake and has it too. EMBO Rep 15:622-4

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