Molecular Pharmacology of Tumor and Virus Inhibitors

肿瘤和病毒抑制剂的分子药理学

• 批准号: 6894590
• 负责人: Arthur Patrick Grollman
• 金额: $ 6.97万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894590
• 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，阐明的总体目标 致癌作用的主要事件。我们的目标是阐明分子机制 酶识别，修复和催化DNA合成，过去的内源性 和DNA中的外源损害。这个跨学科的主要主题 研究是在受损的DNA结构与 参与DNA复制和修复的酶的功能。走向这个 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。 我们的具体目的是（a）探索所选人的角色和功能 DNA聚合酶（POL B，POL K和POL在诱变和DNA修复中，（B）至 确定选定的DNA糖基酶结合的三维结构 与它们的同源DNA底物，以随后在阐明功能中使用 与氧化受损的DNA相互作用的氨基酸残基的（C） 分离株和表征真核体中先前未鉴定的DNA糖基酶 细胞和（d）建立定义的Bistrand病变的诱变潜力 在修复这种损伤的DNA和分子机制中；在 平行，测量Bistrand诱导基因表达的全局变化 病变细胞内转换为双链断裂。