STRUCTURAL STUDIES OF DNA REPAIR PROTEINS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，不一定是研究者的机构。 DNA可以被环境和细胞内因子破坏。DNA修复失败会导致遗传不稳定和突变，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修复蛋白的结构研究对于破译这些重要机制至关重要。下面简要介绍要研究的生物学问题。首先，了解导致遗传性癌症的基因产物如何相互作用。这些结构研究将大大有助于DNA损伤信号和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。第二，在癌症中发现了突变的肿瘤抑制因子，但其功能尚不清楚。为了更好地了解正常和病变细胞过程中这些未表征的肿瘤抑制因子，我们希望利用X射线晶体学阐明它们的三维结构。第三，当DNA暴露于遗传毒性物质，包括来自太阳的紫外线和有毒化学物质时，最早的细胞事件之一是识别受损的DNA。DNA传感器蛋白如何识别和稳定地结合到各种受损的DNA结构的结构见解将是非常宝贵的，在了解人类疾病的病因与基因组不稳定性，包括癌症和精神发育迟滞。

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.