Agents which induce DNA damage are known to induce mutations, malignant transformation, and loss of cell viability. A better understanding of the carcinogenic process as well as how therapeutic agents used in the treatment of malignancy induce cell killing requires a knowledge of how the cell interacts with DNA damage, i.e. DNA repair. Most previously reported studies have focused on repair events at the DNA level. However, little is known about how the chromatin is modified for DNA excision repair. Preliminary studies from this laboratory suggest that the technique of premature chromosome condensation (PCC) can be a poweful tool for probing chromosome events associated with DNA repair. The purpose of this project is to combine the use of the PCC technique, DNA elution, DNA repair inhibitors, DNA repair deficient cell lines, and immunological techniques to better understand chromatin aspects of repair.
Four specific aims are proposed: (1) Characterize the kinetics of early and late chromatin events associated with DNA excision repair after ultraviolet (UV) light irradiation; (2) Determine which types of DNA lesions induce a chromosome response (i.e. DNA monofunctional adducts, DNA-DNA and DNA-protein crosslinks, long patch vs short patch repair inducers); (3) Determine whether specific chromatin events can be inhibited by agents which block topoisomerase activity, repair synthesis, ligase activity or poly ADP ribosylation; (4) Explore the use of immunological procedures to specific factors associated with DNA repair (e.g. DNA polymerase Alpha) to localize and characterize repair events within chromosomes. This combination of approaches should yield significant new information into the chromatin events associated with DNA excision repair and should shed new light on how cells respond to DNA damage.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Study Section (RAD)
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University of Texas MD Anderson Cancer Center
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Hittelman, W N (1990) Direct measurement of chromosome repair by premature chromosome condensation. Prog Clin Biol Res 340B:337-46
Petkovic, I; Agbor, P; Hittelman, W N (1989) Simultaneous cell type identification and premature chromosome condensation analysis in a case of multiple myeloma. Cancer Genet Cytogenet 39:203-17
Hittelman, W N; Petkovic, I; Agbor, P (1988) Improvements in the premature chromosome condensation technique for cytogenetic analysis. Cancer Genet Cytogenet 30:301-12
Hittelman, W N; Agbor, P; Petkovic, I et al. (1988) Detection of leukemic clone maturation in vivo by premature chromosome condensation. Blood 72:1950-60
Wlodek, D; Hittelman, W N (1988) The relationship of DNA and chromosome damage to survival of synchronized X-irradiated L5178Y cells. II. Repair. Radiat Res 115:566-75
Wlodek, D; Hittelman, W N (1988) The relationship of DNA and chromosome damage to survival of synchronized X-irradiated L5178Y cells. I. Initial damage. Radiat Res 115:550-65
Hittelman, W N; Sen, P (1988) Heterogeneity in chromosome damage and repair rates after bleomycin in ataxia telangiectasia cells. Cancer Res 48:276-9
Beisker, W; Hittelman, W N (1988) Measurement of the kinetics of DNA repair synthesis after uv irradiation using immunochemical staining of incorporated 5-bromo-2'-deoxyuridine and flow cytometry. Exp Cell Res 174:156-67
Zwelling, L A; Estey, E; Silberman, L et al. (1987) Effect of cell proliferation and chromatin conformation on intercalator-induced, protein-associated DNA cleavage in human brain tumor cells and human fibroblasts. Cancer Res 47:251-7
Sognier, M A; Hittelman, W N (1986) Mitomycin-induced chromatid breaks in HeLa cells: a consequence of incomplete DNA replication. Cancer Res 46:4032-40

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