STRUCTURAL STUDIES OF DNA REPAIR PROTEINS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 DNA既可以被环境因素破坏，也可以被细胞内因素破坏。如果不能修复DNA，可能会导致基因不稳定和突变，从而导致包括癌症在内的各种人类疾病。因此，了解DNA修复蛋白的功能机制具有重要的生物学意义和临床意义。用X射线结晶学研究DNA修复蛋白的结构对于破译这些重要的机制至关重要。对将要研究的生物学问题的简要描述如下。首先，为了了解导致遗传性癌症的基因产物是如何相互作用的。这样的结构研究将大大有助于DNA损伤信号和DNA修复复合体的招募是如何协调的，以及它们的突变可能如何导致癌症。其次，有一些肿瘤抑制基因的突变在癌症中被发现，但其功能尚不清楚。为了更好地了解这些未知的肿瘤抑制因子在正常和疾病的细胞过程中的作用，我们希望利用X射线结晶学来阐明它们的三维结构。第三，当DNA暴露在遗传毒性物质中时，包括来自太阳的紫外线和有毒化学物质，最早的细胞事件之一是识别受损的DNA。深入了解DNA传感器蛋白如何识别并稳定结合各种受损的DNA结构，对于理解与基因组不稳定有关的人类疾病的病因学将是非常宝贵的，包括癌症和智力低下。

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.