CYCLE-DEPENDENT MECHANISMS OF CHEMICAL CARCINOGENESIS

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Malignant transformation requires cell proliferation and is specifically dependent on DNA replication Structural damage inflicted on genetic material by chemical carcinogens is necessary but not sufficient to initiate chemical carcinogenesis. Only if DNA damage not eliminated by repair processes can be converted into transforming lesions. The probability that a cell will be transformed by a chemical carcinogen is related not only to the extent of DNA damage (modulated by dose and repair) in specific DNA sites, but also to molecular mechanisms of replication of structurally altered DNA. The process of neoplastic transformation is genetically determined and shares mechanistic characteristics with mutagenesis, including S phase dependence. Higher susceptibility to malignant transformation is observed when cells are treated in early S phase, as compared to other points in the cell cycle; cells may be susceptible only to damage occurring at this time int eh cycle. This may be due to damage to specific DNA sites at or close to its time of replication in early S phase. Alternatively, inability to delay the onset of replication or a deficiency in excision repair during the S phase would also increase the probability of fixation of such a genetic alteration, independently of the timing of replication of the damaged DNA sequence. In this Program Project we will pool our individual expertise to obtain experimental evidence to support or refute these hypotheses. We will clone DNA sites replicated in early S phase, particularly those that are associated with the nuclear matrix as possible sites of preferential genetic damage early in carcinogenesis. We will assess of these NA clones contain DNA replication start sites. We will determine whether cell cycle checkpoints project against S-phase dependent clastogenesis , or alteration of growth arrest capability makes cells more vulnerable to gene amplification. In each project the emphasis will be on understanding the effect of cell cycle on these aspects of carcinogenesis.