MOLECULAR PHARMACOLOGY OF TUMOR AND VIRUS INHIBITORS

这项研究调查了DNA损伤与过程的关系 参与了化学诱变。核苷加合物，衍生自 化学致癌物、化学治疗剂及电离产品 辐射，将结合在特定的位置，合成 寡聚脱氧核苷酸。这些病变的诱变光谱将是 在哺乳动物细胞和细菌中确定。 将开发新的保护组，允许特定地点 将碱敏加合物掺入寡脱氧核苷酸。 引入交联剂和预选位置的合成方法 在双链DNA中将被建立。化学改性 寡核苷酸将被用来探索分子机制，通过 哪些DNA聚合酶复制损坏的模板并描绘出 DNA复制和修复的过程，特别是 化学诱变。 将开发允许化学修饰的实验系统 DNA被整合到染色体DNA中，随后拯救 突变分析。受损的DNA将被检查其是否有能力 加强同源重组。它们之间的精确关系 DNA损伤的数量和位置与SOS反应的诱导 将会被确定。物理方法，包括2D-核磁共振和分子 模型建筑，将用来建立三维 化学修饰的寡核苷酸在溶液中的结构。 拟放射剂博莱霉素的致突变性可能源于 碱基、3-磷酸乙醇酸残基和/或核苷碱基 当这种抗生素与DNA反应时产生的丙烯。我们会 检测两种结构损伤的致突变性，并表征 核苷碱基丙烯与DNA反应生成加合物。 这项研究的意义在于建立一个分子基础 对于各种类型的DNA损伤和在 证明了它与DNA修复的关系。这些现象是 对所涉及的主要事件的理解至关重要 化学致癌。

This research investigates the relationship of DNA damage to processes involved in chemical mutagenesis. nucleoside adducts, derived from chemical carcinogens, chemotherapeutic agents and products of ionizing radiation, will be incorporated, site-specifically, into synthetic oligodeoxynucleotides. The mutagenic spectra of these lesions will be determined in mammalian cells and bacteria. New protecting groups will be developed that will permit site-specific incorporation of alkali-sensitive adducts into oligodeoxynucleotides. Synthetic methods for introducing crosslinks and pre-selected positions in duplex DNA will be established. Chemically-modified oligodeoxynucleotides will be used to explore molecular mechanisms by which DNA polymerases copy damaged templates and to delineate the process of DNA replication and repair, with special reference to chemical mutagenesis. Experimental systems will be developed which allow chemically-modified DNA to be integrated into chromosomal DNA and subsequently rescue for mutational analysis. Damaged DNA will be examined for its ability to enhance homologous recombination. The precise relationship between the number and location of DNA lesions and the induction of the SOS response will be determined. Physical methods, including 2D-NMR and molecular model building, will be used to establish the three dimensional structure of chemically-modified oligodeoxynucleotides in solution. The mutagenicity of the radiomimetic agent, bleomycin, could arise from the abasic sites, 3-phosphoglycolate residues, and/or nucleoside base propenals produced when this antibiotic reacts with DNA. We will examine the mutagenicity of the two structural lesions and characterize the adducts formed when nucleoside base propenals react with DNA. The significance of this research lies in establishing a molecular basis for the mutagenic effects of various types of DNA damage and in demonstrating its relationship to DNA repair. These phenomena are fundamental to an understanding of the primary events involved in chemical carcinogenesis.