The applicant proposes to investigate the molecular basis of the human genetic disease, ataxia telangiectasia (A-T). A-T is an autosomal recessive human genetic disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, enhanced sensitivity to ionizing radiation and increased cancer risk. In addition, patients exhibit immune deficiencies, signs of premature aging and underdevelopment of certain organs and tissues. The applicant will focus on the apparent abnormal response of cells from A-T patients to DNA-damaging agents. The applicant postulates that this abnormal response leads to the enhanced genetic instability associated with the disease. The applicants have focused on two abnormalities in the response of A-T cells to DNA damage: failure to phosphorylate certain key proteins (e.g. RPA); and abnormal repair of DNA double-strand breaks. They propose a model for the role of ATM in these responses: DMA strand breaks are produced during aberrant replication of UV-damaged DNA templates; ATM binds to DNA ends, activating the protein kinase and protection the ends from excessive degradation; ATM phosphorylates RPA, reducing the affinity of RPA for ssDNA and facilitating the pairing of strands during DSB repair. The goal is to understand how the A-T defect leads to enhanced genomic instability in response to UV and IR.
The specific aims of this project are: (1) To determine the functional consequences of UV-induced RPA hyperphosphorylation. (2) To determine whether ATM participates directly in DSB repair. (3) To determine whether ARM-mediated RPA hyperphosphorylation plays a role in DSB repair. (4) To determine the role of ATM in UV-induced RPA hyperphosphorylation. The ultimate goal of this project is to define the underlying defect in the response of A-T cells to UV/IR with the hope that this understanding will lead to the development of strategies for treating this devastating genetic neurological disease of childhood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS034782-04A1
Application #
6193038
Study Section
Radiation Study Section (RAD)
Program Officer
Spinella, Giovanna M
Project Start
1997-01-01
Project End
2003-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$263,995
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Thompson, Eric G; Fares, Hanna; Dixon, Kathleen (2012) BRCA1 requirement for the fidelity of plasmid DNA double-strand break repair in cultured breast epithelial cells. Environ Mol Mutagen 53:32-43
Rahal, Elias A; Henricksen, Leigh A; Li, Yuling et al. (2010) ATM regulates Mre11-dependent DNA end-degradation and microhomology-mediated end joining. Cell Cycle 9:2866-77
Rahal, Elias A; Henricksen, Leigh A; Li, Yuling et al. (2008) ATM mediates repression of DNA end-degradation in an ATP-dependent manner. DNA Repair (Amst) 7:464-75
Robison, Jacob G; Bissler, John J; Dixon, Kathleen (2007) Replication protein A is required for etoposide-induced assembly of MRE11/RAD50/NBS1 complex repair foci. Cell Cycle 6:2408-16
Robison, Jacob G; Dixon, Kathleen; Bissler, John J (2007) Cell cycle-and proteasome-dependent formation of etoposide-induced replication protein A (RPA) or Mre11/Rad50/Nbs1 (MRN) complex repair foci. Cell Cycle 6:2399-407
Patrick, Steve M; Oakley, Greg G; Dixon, Kathleen et al. (2005) DNA damage induced hyperphosphorylation of replication protein A. 2. Characterization of DNA binding activity, protein interactions, and activity in DNA replication and repair. Biochemistry 44:8438-48
Robison, Jacob G; Lu, Lu; Dixon, Kathleen et al. (2005) DNA lesion-specific co-localization of the Mre11/Rad50/Nbs1 (MRN) complex and replication protein A (RPA) to repair foci. J Biol Chem 280:12927-34
Nuss, Jonathan E; Patrick, Steve M; Oakley, Greg G et al. (2005) DNA damage induced hyperphosphorylation of replication protein A. 1. Identification of novel sites of phosphorylation in response to DNA damage. Biochemistry 44:8428-37
Dixon, Kathleen; Kopras, Elizabeth (2004) Genetic alterations and DNA repair in human carcinogenesis. Semin Cancer Biol 14:441-8
Robison, Jacob G; Elliott, James; Dixon, Kathleen et al. (2004) Replication protein A and the Mre11.Rad50.Nbs1 complex co-localize and interact at sites of stalled replication forks. J Biol Chem 279:34802-10

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