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
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010283-09
Application #
7338299
Study Section
(EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Daniel, Jeremy A; Nussenzweig, Andre (2013) The AID-Induced DNA Damage Response in Chromatin. Mol Cell 50:309-21
Callen, Elsa; Di Virgilio, Michela; Kruhlak, Michael J et al. (2013) 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153:1266-80
Bunting, Samuel F; Callén, Elsa; Kozak, Marina L et al. (2012) BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell 46:125-35
Daniel, Jeremy A; Nussenzweig, André (2012) Roles for histone H3K4 methyltransferase activities during immunoglobulin class-switch recombination. Biochim Biophys Acta 1819:733-8
Callen, Elsa; Faryabi, Robert B; Luckey, Megan et al. (2012) The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration. Immunity 37:971-85
Schotta, Gunnar; Sengupta, Roopsha; Kubicek, Stefan et al. (2008) A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev 22:2048-61
Takizawa, Makiko; Tolarova, Helena; Li, Zhiyu et al. (2008) AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development. J Exp Med 205:1949-57
Reina-San-Martin, Bernardo; Chen, Junjie; Nussenzweig, Andre et al. (2007) Enhanced intra-switch region recombination during immunoglobulin class switch recombination in 53BP1-/- B cells. Eur J Immunol 37:235-9
Ramiro, Almudena; San-Martin, Bernardo Reina; McBride, Kevin et al. (2007) The role of activation-induced deaminase in antibody diversification and chromosome translocations. Adv Immunol 94:75-107
Kuznetsov, Sergey; Pellegrini, Manuela; Shuda, Kristy et al. (2007) RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J Cell Biol 176:581-92

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