Human cells contain singular DAN repair pathways to excise critical lesions from DNA. In individuals with clinical syndromes predisposing to malignancy, the capacity to excise these lesions is impaired. This research proposal is designed to continue our investigations on: (1) the biochemical and molecular mechanisms through which normal human cells regulate excision repair genes during cell proliferation; and (2) whether aberrations in regulatory mechanisms of DNA repair may provide a molecular mechanism for the cellular sensitivities of individuals who may be cancer prone. In particular, in this research proposal, we plan to determine the translational regulation of DNA repair enzymes during cell proliferation and after carcinogen exposure and subsequent DNA repair. Further, we seek to determine the immunological relationships of human DNA repair enzymes. For these studies we have developed a series of monoclonal antibodies to human placental uracil DNA glycosylases. Normal human cells and cells from cancer prone individuals will be used in all studies. The objectives of this proposal are: 1. To examine the immunological relationships and amino acid sequence homologies of uracil DNA glycosylases isolated from normal human calls and cells from cancer prone individuals. These relationships will be examined by radioimmunoassay using our monoclonal antibodies. 2. To determine the translational regulation of uracil DNA glycosylases during cell proliferation of normal human cells and cells from cancer prone individuals. Using our monoclonal antibodies, glycosylase regulation will be examined by 2 dimensional gel electrophoresis of immunoreactive species as well as by in vitro translation analysis using isolated poly (A) containing mRNA. 3. To determine the translational regulation of uracil DNA glycosylases in quiescent and in proliferating human cells after DNA damage and subsequent DNA repair.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029414-05
Application #
3168703
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-02-01
Project End
1987-01-31
Budget Start
1985-02-01
Budget End
1986-01-31
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Sirover, M A (1996) Minireview. Emerging new functions of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in mammalian cells. Life Sci 58:2271-7
Wurzer, J C; Tallarida, R J; Sirover, M A (1994) New mechanism of action of the cancer chemotherapeutic agent 5-fluorouracil in human cells. J Pharmacol Exp Ther 269:39-43
Weng, Y; Sirover, M A (1993) Developmental regulation of the base excision repair enzyme uracil DNA glycosylase in the rat. Mutat Res 293:133-41
Mansur, N R; Meyer-Siegler, K; Wurzer, J C et al. (1993) Cell cycle regulation of the glyceraldehyde-3-phosphate dehydrogenase/uracil DNA glycosylase gene in normal human cells. Nucleic Acids Res 21:993-8
Mauro, D J; De Riel, J K; Tallarida, R J et al. (1993) Mechanisms of excision of 5-fluorouracil by uracil DNA glycosylase in normal human cells. Mol Pharmacol 43:854-7
Meyer-Siegler, K; Rahman-Mansur, N; Wurzer, J C et al. (1992) Proliferative dependent regulation of the glyceraldehyde-3-phosphate dehydrogenase/uracil DNA glycosylase gene in human cells. Carcinogenesis 13:2127-32
Meyer-Siegler, K; Mauro, D J; Seal, G et al. (1991) A human nuclear uracil DNA glycosylase is the 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U S A 88:8460-4
Seal, G; Tallarida, R J; Sirover, M A (1991) Purification and properties of the uracil DNA glycosylase from Bloom's syndrome. Biochim Biophys Acta 1097:299-308
Cool, B L; Sirover, M A (1990) Proliferation-dependent regulation of DNA glycosylases in progeroid cells. Mutat Res 237:211-20

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