STRUCTURAL STUDIES OF DNA REPAIR PROTEINS

DNA 修复蛋白的结构研究

• 批准号: 8169225
• 负责人: NIKOLA P PAVLETICH
• 金额: $ 5.46万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169225
• 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; repaired; sensor; 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 DNA 可能会受到环境因素和细胞内因素的损害。 DNA 修复失败可能会导致遗传不稳定和突变，从而导致各种人类疾病，包括癌症。因此，了解 DNA 修复蛋白的功能机制具有重要的生物学和临床意义。使用 X 射线晶体学对 DNA 修复蛋白进行结构研究对于破译这些重要机制至关重要。要研究的生物学问题的简要描述如下。首先，了解导致遗传性癌症的基因产物如何相互作用。此类结构研究将极大地有助于了解 DNA 损伤信号传导和 DNA 修复复合物的招募如何协调以及它们的突变如何导致癌症。其次，在癌症中发现了一些肿瘤抑制因子的突变，但其功能尚不清楚。为了更好地了解正常和患病细胞过程中这些未表征的肿瘤抑制因子，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暴露于包括太阳紫外线和有毒化学物质在内的基因毒性剂时，最早的细胞事件之一就是识别受损的DNA。关于 DNA 传感器蛋白如何识别并稳定结合各种受损 DNA 结构的结构见解对于理解与基因组不稳定性相关的人类疾病（包括癌症和智力障碍）的病因学将具有无价的价值。