STRUCTURAL STUDIES OF DNA REPAIR PROTEINS

DNA 修复蛋白的结构研究

• 批准号: 7955104
• 负责人: NIKOLA P PAVLETICH
• 金额: $ 27.63万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955104
• 关键词: Binding; Biological; Cell physiology; Computer Retrieval of Information on Scientific Projects Database; Crystallography; DNA; DNA Damage; DNA Repair; DNA Structure; DNA repair protein; Etiology; Event; Failure; Funding; Genetic; Genomic Instability; Grant; Inherited; Institution; Lead; Malignant Neoplasms; Mental Retardation; Mutagens; Mutation; Poison; Proteins; Repair Complex; Research; Research Personnel; Resources; Signal Transduction; Source; The Sun; Tumor Suppressor Proteins; Ultraviolet Rays; United States National Institutes of Health; X-Ray Crystallography; clinically relevant; human disease; insight; protein function; sensor; structural biology; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DNA can be damaged by both environmental and intra-cellular agents. Failure to repair DNA can cause genetic instability and mutations that lead to various human diseases, including cancer. Therefore, understanding the mechanisms by which DNA repair proteins function have important biological and clinical relevance. Structural studies of DNA repair proteins using X-ray crystallography are critical in deciphering these important mechanisms. Brief descriptions of the biological questions to be studied are as follows. First, to understand how the gene products that cause inherited forms of cancers, interact with one another. Such structural studies will contribute greatly to how DNA damage signaling and recruitment of DNA repair complexes are coordinated and how their mutations may lead to cancer. Second, there are tumor suppressors whose mutations are found in cancer, but whose functions are not yet known. In order to gain a better insight into these uncharacterized tumor suppressors in normal and diseased cellular processes, we wish to elucidate their three-dimensional structures using x-ray crystallography. Third, when DNA is exposed to genotoxic agents including ultraviolet light from the sun and toxic chemicals, one of the earliest cellular event is recognition of the damaged DNA. Structural insights into how DNA-sensor proteins recognize and bind stably to various damaged DNA-structures will be invaluable in understanding the etiology of human diseases related to genomic instability, including cancer and mental retardation.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 环境和细胞内药物都可能损坏DNA。无法修复DNA会导致遗传不稳定性和突变，从而导致包括癌症在内的各种人类疾病。因此，了解DNA修复蛋白功能具有重要的生物学和临床相关性的机制。使用X射线晶体学对DNA修复蛋白的结构研究对于破译这些重要机制至关重要。对要研究的生物学问题的简要描述如下。首先，要了解引起遗传形式癌症的基因产品如何相互作用。这种结构研究将极大地促进DNA损伤信号传导和DNA修复复合物的募集如何协调，以及它们的突变如何导致癌症。其次，有一些肿瘤抑制剂的突变是在癌症中发现的，但其功能尚不清楚。为了在正常和患病的细胞过程中更好地了解这些未表征的肿瘤抑制剂，我们希望使用X射线晶体学阐明它们的三维结构。第三，当DNA暴露于包括太阳和有毒化学物质的紫外线在内的遗传毒性剂时，最早的细胞事件之一是识别受损的DNA。关于DNA传感器蛋白如何与各种受损的DNA结构稳定识别和结合的结构见解对于理解与基因组不稳定性有关的人类疾病的病因，包括癌症和智力低下。