CHEMICAL CARCINOGENESIS AND CELL PROLIFERATION

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The objective of this research project is to investigate the molecular mechanisms underlying the relationship between cell proliferation and chemical carcinogenesis. It proposes to study how and where DNA replication is involved in the multi-stage transition of a cell to the malignant phenotype. One of the technical approaches of this project is the isolation of eukaryotic replication complexes which can be used to study DNA replication in vitro as well as to probe the mechanisms of action of chemical carcinogens. Efforts will be directed towards further purification and characterization of the constituents of the eukaryotic replication complex, analysis of the effect of carcinogens on the activity of replication complexes in vitro and isolation of DNA sequences that replicate early in the S phase. DNA at the replication complex is preferentially methylated by chemical carcinogens and this is due to a higher susceptibility of replication forks to chemical alkylation. The mechanisms responsible for this phenomemon will be investigated. Furthermore, the generality of such observations in relation to other carcinogens will be verified. Another technical approach in this project is the in vitro localization of DNA adducts with the help of specific antibodies and the electron microscope. This will allow the study of the relationship between replication forks and carcinogen damage and provide insight about the mechanisms of lesion bypass by the replication machinery. The studies in this project are directed towards a better understanding of the biochemistry of cell transformation and the biological mechanisms responsible for the initiation of cancer. The long-term objective of the above studies is to elucidate the higher frequency of transformation observed when cells are treated with carcinogens in S phase.