Abstract

The goals of this research proposal include the characterization of the DNA repair properties of xeroderma pigmentosum (XP) fibroblasts that express one or more of the E. coli uvr genes (uvrA, uvrB, uvrC) stably integrated into their chromosomes. A number of independent and unique phenotypic properties of these clones of XP fibroblast cell lines include: peptide maps of the Uvr proteins, structure of the integrated E. coli uvr genes, cellular localization of the respective Uvr proteins, enzymatic and host cell reactivation of damaged genes by complementing microinjected Uvr proteins and survival in the presence of DNA damaging agents. The effects of specific nuclear and cytoplasmic localization of individual repair phenotypes will be examined as well as the effects of varying the expressible concentrations of the Uvr proteins through methotrexate amplification of a co- transfected DHFR gene. An assay is being developed as a component of a feasibility study for measuring the DNA repair potential in man through an assessment of the ability of fresh lymphocytes to restore the activity of a specific gene inactivated, in this case, by ultraviolet light.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031110-07
Application #
3279051
Study Section
Biochemistry Study Section (BIO)
Project Start
1982-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Wei, Q; Matanoski, G M; Farmer, E R et al. (1995) DNA repair capacity for ultraviolet light-induced damage is reduced in peripheral lymphocytes from patients with basal cell carcinoma. J Invest Dermatol 104:933-6
Wei, Q; Matanoski, G M; Farmer, E R et al. (1994) DNA repair related to multiple skin cancers and drug use. Cancer Res 54:437-40
Wang, J; Mueller, K L; Grossman, L (1994) A mutational study of the C-terminal zinc-finger motif of the Escherichia coli UvrA protein. J Biol Chem 269:10771-5
Wei, Q; Matanoski, G M; Farmer, E R et al. (1994) DNA repair and susceptibility to basal cell carcinoma: a case-control study. Am J Epidemiol 140:598-607
Wei, Q; Matanoski, G M; Farmer, E R et al. (1994) Vitamin supplementation and reduced risk of basal cell carcinoma. J Clin Epidemiol 47:829-36
Wang, J; Grossman, L (1993) Mutations in the helix-turn-helix motif of the Escherichia coli UvrA protein eliminate its specificity for UV-damaged DNA. J Biol Chem 268:5323-31
Wei, Q; Matanoski, G M; Farmer, E R et al. (1993) DNA repair and aging in basal cell carcinoma: a molecular epidemiology study. Proc Natl Acad Sci U S A 90:1614-8
Thiagalingam, S; Grossman, L (1993) The multiple roles for ATP in the Escherichia coli UvrABC endonuclease-catalyzed incision reaction. J Biol Chem 268:18382-9
Claassen, L A; Grossman, L (1991) Deletion mutagenesis of the Escherichia coli UvrA protein localizes domains for DNA binding, damage recognition, and protein-protein interactions. J Biol Chem 266:11388-94
Thiagalingam, S; Grossman, L (1991) Both ATPase sites of Escherichia coli UvrA have functional roles in nucleotide excision repair. J Biol Chem 266:11395-403

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