The candidate plans to pursue a research career focused on the chemistry, enzymology, and genetics of DNA damage and repair with both immediate and long-term emphasis on the application of molecular biology and genetic techniques to address fundamentally important problems in the area of radiation biology and carcinogenesis. An important component of these goals, and an immediate objective, is to expand my current research expertise by becoming more proficient in the techniques and applications of gene isolation, identification, and manipulation. Another immediate goal is to acquire expertise in the application of 2D NMR and computer modelling techniques for deducing DNA structures containing radiation-induced damages. In both cases this can be accomplished on the Emory campus through close contract and collaborations with two of my colleagues. A Research Career Development Award will free substantial time commitments (currently devoted to teaching and university service) to allow almost full- time (85% or greater) pursuit of my research goals which would include a sufficient amount of time to gain proficiency in the areas cited above. The research time generated by the RCDA will be particularly important for carrying out these studies during the academic year. The RCDA would also contribute substantially towards the realization of an important, long-term goal for this candidate; to provide an excellent research training environment for graduate students and postdoctoral fellows. Emory University is rapidly developing its basic science research program, a component of which will be the completion of a new biological sciences research building that my laboratory will occupy at the end of 1989. The goal of the candidate's research proposal is to gain an understanding of the role mediate by redoxyendonuclease (RE), a DNA repair enzyme that recognizes a variety of base damage products, in the eukaryotic cellular response to oxidative and radiation-induced damaged of DNA.
The specific aims are directed towards gaining an understanding of the enzymology, genetics, and regulation of these enzymes in yeast and human cells. The cloning and characterization of the yeast RE gene will permit study of the regulation of this enzyme in response to radiation-induced DNA damage in yeast cells. The gene probes and antibodies generated in the yeast RE studies may have utility for probing RE's from other species, including humans. A long-term goal of these studies will be to apply the methods and expertise acquired in these studies to characterize other eukaryotic enzymes involved in the repair of oxidative and radiation-induced DNA damage. By uniting biochemical, molecular biological, and genetic approaches, it is anticipated that a more complete understanding of how RE and subsequently, other DNA repair enzymes maintain the genetic stability of eukaryotic cells, including humans, will emerge.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Modified Research Career Development Award (K04)
Project #
5K04CA001441-05
Application #
3071929
Study Section
Radiation Study Section (RAD)
Project Start
1989-04-01
Project End
1994-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Augeri, L; Hamilton, K K; Martin, A M et al. (1994) Purification and properties of yeast redoxyendonuclease. Methods Enzymol 234:102-15
Zhou, W; Doetsch, P W (1993) Effects of abasic sites and DNA single-strand breaks on prokaryotic RNA polymerases. Proc Natl Acad Sci U S A 90:6601-5
Hasegawa, S L; Doetsch, P W; Hamilton, K K et al. (1991) DNA binding properties of YB-1 and dbpA: binding to double-stranded, single-stranded, and abasic site containing DNAs. Nucleic Acids Res 19:4915-20
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Strickland, J A; Marzilli, L G; Puckett Jr, J M et al. (1991) Purification and properties of nuclease SP. Biochemistry 30:9749-56
Doetsch, P W; Cunningham, R P (1990) The enzymology of apurinic/apyrimidinic endonucleases. Mutat Res 236:173-201
Lenz, J; Okenquist, S A; LoSardo, J E et al. (1990) Identification of a mammalian nuclear factor and human cDNA-encoded proteins that recognize DNA containing apurinic sites. Proc Natl Acad Sci U S A 87:3396-400