ZIA BC 010959 (ZIA) | |||
---|---|---|---|
Title | Relationship between DNA damage detection and signaling | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Nussenzweig, Andre | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,309,141 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Ataxia Telangiectasia (50.0%) Cancer (100.0%) |
Leukemia (25.0%) Nervous System (50.0%) Non Hodgkins Lymphoma (25.0%) |
||
Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Endogenous Factors in the Origin and Cause of Cancer |
|||
Abstract | |||
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. |