Molecular Pharmacology of Tumor and Virus Inhibitors

肿瘤和病毒抑制剂的分子药理学

• 批准号: 7008541
• 负责人: Arthur Patrick Grollman
• 金额: $ 41.14万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-01-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008541
• 关键词: DNA damage; DNA directed DNA polymerase; DNA repair; DNA replication; N glycosidase; X ray crystallography; bleomycin; enzyme activity; mass spectrometry; microarray technology; mutagens; pharmacogenetics

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.

描述：（由申请人提供）该研究计划的重点是 DNA 损伤的生物学后果，总体目标是阐明 致癌过程中的主要事件。我们的目标是阐明分子机制 通过酶识别、修复和催化 DNA 合成，超越内源性 以及 DNA 的外源性损伤。这个跨学科的一个主要主题 研究的目的是建立受损 DNA 结构与 参与 DNA 复制和修复的酶的功能。朝这个方向 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，最近出现的强大新技术 结构和功能基因组学研究。 我们的具体目标是 (a) 探索选定人类的角色和功能 DNA 聚合酶（诱变和 DNA 修复中的 Pol B、Pol K 和 Pol，(b) 至 确定所选 DNA 糖基化酶结合的三维结构 其同源 DNA 底物，用于随后阐明功能 与氧化损伤的 DNA 相互作用的氨基酸残基，(c) 分离并表征真核生物中先前未鉴定的 DNA 糖基化酶 细胞，以及（d）确定确定的双链损伤的诱变潜力 DNA 和修复此类损伤的分子机制；在 平行，测量双链时诱导的基因表达的全局变化 损伤在细胞内转化为双链断裂。