Human cells contain singular DNA 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 pathways 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 continue our examination of structural alterations in DNA repair enzymes from hypermutable cells from cancer prone individuals. For these studies, we shall use a series of monoclonal antibodies developed in this laboratory to the human placental uracil DNA glycosylase. The objectives of this proposal are: 1) To examine the immunological relationships and amino acid sequence homologies of normal human uracil DNA glycosylase. Through ELISA analyses using a series of three anti-human uracil DNA glycosylase monoclonal antibodies we shall determine the structure of each monoclonal antibody binding site as well as the catalytic and pyrimidine analogue binding sites. 2) To directly demonstrate the specificity and molecular basis for the altered antigenicity of the Bloom's syndrome uracil DNA glycosylase. We shall examine the separate Bloom's syndrome patients as well as determining kinetic alterations of the Bloom's syndrome enzymes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029414-09
Application #
3168706
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-02-01
Project End
1991-12-31
Budget Start
1990-01-01
Budget End
1991-12-31
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Wang, X; Sirover, M A; Anderson, L E (1999) Pea chloroplast glyceraldehyde-3-phosphate dehydrogenase has uracil glycosylase activity. Arch Biochem Biophys 367:348-53
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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