Molecular Pharmacology of Tumor and Virus Inhibitors

描述：（由申请人提供）这项研究计划的重点是 DNA损伤的生物学后果，总体目标是阐明 致癌的主要事件。我们的目标是阐明分子机制 酶识别，修复和催化DNA合成，过去内源性 和外源性DNA损伤。这一跨学科的主要主题 研究的目的是建立受损DNA的结构与 参与DNA复制和修复的酶的功能。为实现这一 最后，我们将使用X射线晶体学，质谱蛋白质组学， 微阵列分析，强大的新技术，最近已经出现，通过 结构和功能基因组学研究。 我们的具体目标是：（a）探讨选定的人的角色和功能 DNA聚合酶（Pol B、Pol K和Pol）在诱变和DNA修复中的作用，（B）至 确定结合的选定DNA糖基化酶的三维结构 与其同源DNA底物结合，以便随后用于阐明功能 与氧化损伤的DNA相互作用的氨基酸残基，（c） 真核生物中以前未鉴定DNA糖基化酶的分离和鉴定 细胞，和（d）确定确定的双链病变的致突变潜力 在DNA和修复这种损伤的分子机制中; 平行，以测量当双链 损伤在细胞内转化为双链断裂。

DESCRIPTION: (PROVIDED BY APPLICANT) This research program focuses on the biological consequences of DNA damage with the overall goal of elucidating primary events in carcinogenesis. Our goal is to elucidate molecular mechanisms by which enzymes recognize, repair, and catalyze DNA synthesis, past endogenous and exogenous damage in DNA. A principal theme of this interdisciplinary research is to establish relationships between the structure of damaged DNA and the function of enzymes involved in DNA replication and repair. Towards this end, we will use X-ray crystallography, mass spectrometry proteomics, microarray analysis, powerful new techniques that recently have emerged through structural and functional genomics research. Our specific aims are (a) to explore the role and function(s) of selected human DNA polymerases (Pol B, Pol K, and Pol in mutagenesis and DNA repair, (b) to determine the three-dimensional structures of selected DNA glycosylases bound to their cognate DNA substrates for subsequent use in elucidating the functions of amino acid residues that interact with oxidatively damaged DNA, (c) to isolate and characterize previously unidentified DNA glycosylases in eukaryotic cells, and (d) to establish the mutagenic potential of defined bistrand lesions in DNA and the molecular mechanism(s) by which such damage is repaired; in parallel, to measure global changes in gene expression induced when bistrand lesions are converted intracellularly to double-strand breaks.