We propose to determine the relation between the action of chemical carcinogens and DNA conformation. This work will be carried out by determining the three-dimensional structure of DNA that has been modified by carcinogens and through experiments designed to test the influence of an altered DNA conformation on chemical carcinogen reactivity. The three-dimensional structure determinations will be carried out by crystallizing fragments of synthetic DNA containing 6 to 12 base pairs which have been modified by the action of chemical carcinogens to make an adduct. Among the carcinogens to be tested are acetoxyacetylaminofluorene, aflatoxin, and benzo(a)pyrene. In addition, a number of methylated or alkylated nucleotides will also be synthesized into a double helical DNA fragment. These fragments will be crystallized and their three-dimensional conformation determined in order to determine the relation between DNA conformation and the particular chemical carcinogen. Knowledge of the altered DNA conformation may lead to further understanding of the carcinogenic mechanism. Experiments will also be carried out on the rate at which various carcinogens attack the left-handed Z-DNA compared to right-handed B-DNA. In Z-DNA, the imidazole rings of guanine are exposed and they may react more readily with some carcinogenic agents. We will test the hypothesis that small segments of left-handed Z-DNA may be the active substrate for chemical carcinogens in vivo.
| Mignatti, P; Rifkin, D B (1996) Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 49:117-37 |
| Mignatti, P; Rifkin, D B (1996) Plasminogen activators and angiogenesis. Curr Top Microbiol Immunol 213 ( Pt 1):33-50 |
