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 #
1ZIABC010283-14
Application #
8348962
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2011
Total Cost
$1,333,145
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Yazinski, Stephanie A; Comaills, Valentine; Buisson, Rémi et al. (2017) ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev 31:318-332
Greer, Yoshimi Endo; Gao, Bo; Yang, Yingzi et al. (2017) Lack of Casein Kinase 1 Delta Promotes Genomic Instability - The Accumulation of DNA Damage and Down-Regulation of Checkpoint Kinase 1. PLoS One 12:e0170903
Tubbs, Anthony; Nussenzweig, André (2017) Endogenous DNA Damage as a Source of Genomic Instability in Cancer. Cell 168:644-656
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Chaudhuri, Arnab Ray; Callen, Elsa; Ding, Xia et al. (2016) Erratum: Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 539:456
Nieto-Soler, Maria; Morgado-Palacin, Isabel; Lafarga, Vanesa et al. (2016) Efficacy of ATR inhibitors as single agents in Ewing sarcoma. Oncotarget 7:58759-58767
Li, Minxing; Cole, Francesca; Patel, Dharm S et al. (2016) 53BP1 ablation rescues genomic instability in mice expressing 'RING-less' BRCA1. EMBO Rep 17:1532-1541

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