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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010959-04
Application #
8349248
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
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
Skau, Colleen T; Fischer, Robert S; Gurel, Pinar et al. (2018) Retraction Notice to: FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis. Cell 173:529
Gutierrez-Martinez, Paula; Hogdal, Leah; Nagai, Manavi et al. (2018) Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat Cell Biol 20:413-421
Di Siena, Sara; Campolo, Federica; Gimmelli, Roberto et al. (2018) Atm reactivation reverses ataxia telangiectasia phenotypes in vivo. Cell Death Dis 9:314
Weyemi, Urbain; Paul, Bindu D; Snowman, Adele M et al. (2018) Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis. Nat Commun 9:1526
Gupta, Rajat; Somyajit, Kumar; Narita, Takeo et al. (2018) DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 173:972-988.e23
Ray Chaudhuri, Arnab; Nussenzweig, André (2017) Thwarting endogenous stress: BRCA protects against aldehyde toxicity. EMBO Mol Med 9:1331-1333
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
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
Mijic, Sofija; Zellweger, Ralph; Chappidi, Nagaraja et al. (2017) Replication fork reversal triggers fork degradation in BRCA2-defective cells. Nat Commun 8:859
Ray Chaudhuri, Arnab; Nussenzweig, André (2017) The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 18:610-621

Showing the most recent 10 out of 56 publications