Molecular Pharmacology of Tumor and Virus Inhibitors

描述：(申请者提供)本研究项目侧重于 DNA损伤的生物学后果及其阐明的总体目标 致癌过程中的主要事件。我们的目标是阐明分子机制 酶识别、修复和催化DNA合成的方式，过去是内源性的 以及DNA中的外源性损伤。本交叉学科的一个主要主题 研究旨在确定受损DNA的结构与 参与DNA复制和修复的酶的功能。朝向这个方向 最后，我们将使用X射线结晶学，质谱学蛋白质组学， 微阵列分析，最新出现的强大的新技术 结构和功能基因组学研究。 我们的具体目标是：(A)探索选定的人类(S)的角色和功能 DNA聚合酶(POL B、POL K和POL在突变和DNA修复中，(B)至 确定部分结合的DNA糖基酶的三维结构 与它们的同源DNA底物结合，以便随后用于阐明其功能 与氧化损伤的DNA相互作用的氨基酸残基，(C)到 真核细胞中未知DNA糖基酶的分离和鉴定 细胞，以及(D)确定确定的双链损伤的诱变潜力 DNA和修复这种损伤的分子机制(S)； 平行，以测量双链时诱导的基因表达的全局变化 病变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.