CHEMICAL CARCINOGENESIS AND CELL PROLIFERATION

本研究项目的目的是研究 细胞增殖和细胞凋亡之间的关系 化学致癌作用 它建议研究DNA如何以及在哪里 复制参与了细胞向细胞的多阶段过渡。 恶性表型 该项目的技术方法之一是 分离真核复制复合物，其可用于 研究体外DNA复制以及探索作用机制 化学致癌物。 将努力进一步 真核生物成分的纯化和表征 复制复合物，分析致癌物对活性的影响 复制复合物的体外和DNA序列的分离， 在S期早期复制。 复制复合体中的DNA 优先甲基化的化学致癌物，这是由于 复制叉对化学烷基化的更高敏感性。 的 将研究引起这种现象的机制。 此外，这些意见的一般性， 致癌物质将得到验证。 这个项目的另一个技术方法 DNA加合物的体外定位， 抗体和电子显微镜 这将使研究 复制叉和致癌物损伤之间的关系，并提供 通过复制了解病变旁路的机制 机械. 该项目的研究旨在更好地 了解细胞转化的生物化学和生物学 导致癌症发生的机制。 长期 上述研究的目的是阐明 当细胞在S期用致癌物处理时观察到的转化。

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.