CYCLE-DEPENDENT MECHANISMS OF CHEMICAL CARCINOGENESIS

恶性转化需要细胞增殖， 依赖于DNA复制对基因造成的结构损伤 化学致癌物质是必要的，但不足以 引发化学致癌作用。 只有当DNA损伤没有被 修复过程可以转化为转化损伤。 的 细胞被化学致癌物转化的可能性是 不仅与DNA损伤程度有关（受剂量和修复调节） 在特定的DNA位点，而且复制的分子机制， 结构改变的DNA 肿瘤转化的过程是 基因决定的，并分享机械特征， 诱变，包括S期依赖性。 更高的易感性， 当细胞在早期S期被处理时， 与细胞周期中的其他点相比，细胞可以是 仅对在该周期中此时发生的损坏敏感。 这可能 是由于特定的DNA位点在或接近其时间的损害， S期早期复制。 或者，无法延迟发作 复制或切除修复缺陷在S期将 也增加了这种遗传改变的固定的可能性， 与受损DNA序列复制的时间无关。 在 本计划项目，我们将汇集我们的个人专业知识，以获得 实验证据来支持或反驳这些假设。 我们将克隆 在早期S期复制的DNA位点，特别是那些 与核基质相关的可能的优先位点 在癌症发生早期的遗传损伤。 我们将评估这些NA克隆 含有DNA复制起始位点。 我们将确定细胞周期 针对S期依赖性染色体断裂或改变的检查点项目 生长停滞能力使细胞更容易受到基因 放大 在每个项目中，重点将是了解 细胞周期对这些致癌方面的影响。

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.