Abstract

The structure of oligodeoxynucleotides modified by the environmental carcinogens benzo(a)pyrene diol epoxide and the carcinogens N-2-(acetylamino)fluorene and N2-(amino)fluorene will be determined by the use of two-dimensional NMR spectroscopy. The distances obtained from NOESY data will be used as restraints in molecular mechanics and molecular dynamics calculations. The three dimensional structures of adducts bound to different sequences will be determined to elucidate the effect of sequence on the structure and dynamics of the adducts. Carcinogen-modified oligodeoxynucleotides will be synthesized containing either codon 12 or codon 61 sequences of the mouse and human c-Ha-ras 1 protooncogenes and the structures determined with covalently attached carcinogens at the guanines which are mutated in activating the oncogenes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035251-08
Application #
3172862
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1983-08-01
Project End
1995-05-31
Budget Start
1991-06-01
Budget End
1992-05-31
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Rochester
Department
Type
Schools of Arts and Sciences
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627

  Publications

Rockwell, S; Knisely, J P (1997) Hypoxia and angiogenesis in experimental tumor models: therapeutic implications. EXS 79:335-60
Fountain, M A; Krugh, T R (1995) Structural characterization of a (+)-trans-anti-benzo[a]pyrene-DNA adduct using NMR, restrained energy minimization, and molecular dynamics. Biochemistry 34:3152-61
Eckel, L M; Krugh, T R (1994) Structural characterization of two interchangeable conformations of a 2-aminofluorene-modified DNA oligomer by NMR and energy minimization. Biochemistry 33:13611-24
O'Handley, S F; Sanford, D G; Xu, R et al. (1993) Structural characterization of an N-acetyl-2-aminofluorene (AAF) modified DNA oligomer by NMR, energy minimization, and molecular dynamics. Biochemistry 32:2481-97
Dittrich, K A; Krugh, T R (1991) Analysis of site-specific binding of (+/-)-anti-benzo[a]pyrene diol epoxide to restriction fragments of pBR322 DNA via photochemical mapping. Chem Res Toxicol 4:270-6
Dittrich, K A; Krugh, T R (1991) Mapping of (+/-)-anti-benzo[a]pyrene diol epoxide adducts to human c-Ha-ras1 protooncogene. Chem Res Toxicol 4:277-81
Huang, G J; Krugh, T R (1990) Large-scale purification of synthetic oligonucleotides and carcinogen-modified oligodeoxynucleotides on a reverse-phase polystyrene (PRP-1) column. Anal Biochem 190:21-5
Krugh, T R; Graves, D E; Stone, M P (1989) Two-dimensional NMR studies on the anthramycin-d(ATGCAT)2 adduct. Biochemistry 28:9988-94
Rockwell, S (1989) Tumor radiation responses and tumor oxygenation in aging mice. Exp Gerontol 24:37-48
Rosenberg, L S; Carvlin, M J; Krugh, T R (1986) The antitumor agent mitoxantrone binds cooperatively to DNA: evidence for heterogeneity in DNA conformation. Biochemistry 25:1002-8

Showing the most recent 10 out of 16 publications