Structural Cell Biology of DNA Repair Machines

整体 项目总结/摘要 DNA修复机器是导致致癌突变的中心，是什么预防癌症， 干扰癌症治疗，以及癌症靶向治疗的致命弱点是什么。对于NCI，SBDR 协调DNA修复（DR）的领导者协同工作， 对DR过程的机械理解。SBDR消除了单个实验室内的瓶颈， 促进具有DR不同方面专业知识的多学科研究人员的共同努力。 SBDR项目和核心共同实现了动态多途径的全面知识， 功能性DR机器-只有通过多学科方法才能实现的理解 多个团体的共同努力。SBDR的目标是：1）开发基于结构的、机械的 为动态、多功能DR分子复合物的可操作理解奠定了基础， 癌症生物学、预后和易感性，以及2）能够进行综合的定量和机制分析， DR机器、途径以及与复制和凋亡的交叉点的知识足以帮助 通过弥合从突变序列到系统水平的差距来预测和干预癌症生物学 相关性通过将主要DR和损伤反应途径的分析与复制相结合，SBDR将 提供关于维持遗传完整性的详细和全面的信息， 蛋白质和复合物的途径，网络和信号。我们将以知识为基础， 以及整合DR蛋白相互作用、修饰和 在五个项目中发挥作用。我们需要多方面的基于结构的战略， 多功能复合物的多种活性，如Mre 11-Rad 50-Nbs 1，并定义蛋白质如何在 多重途径与此同时，SBDR项目和核心将实现四个计划目标：1）确定 DR复合物、界面和构象的确定和生物学验证的结构; 2）解剖 通过基于结构的功能分离检查测试DR机器的多功能性 突变和化学抑制剂; 3）定义DR通路相互作用的串扰，并描述和测试如何 进行DR途径选择;以及4）发现由突变或突变引起的合成致死性。 靶向特定DR活性的化学试剂，该活性仅在另一DR缺陷的情况下是致命的， 确定和测试干预和控制癌症DNA损伤生物学结果的具体方法 干预措施。SBDR将通过提供关于如何在癌症生物学中发挥作用的全面的机制知识， 细胞对DNA损伤的反应以及多功能DR蛋白如何在其他DNA过程中起作用。 SBDR将促进对DR突变如何不同地影响癌症易感性的理解， 患者风险。SBDR将帮助使用癌症基因组图谱突变和系统水平相关性的研究 以及通过提供机械和预测性的见解来提供随后的治疗策略。

Overall PROJECT SUMMARY/ABSTRACT DNA repair machines are at the center of what leads to cancer-causing mutations, what prevents cancer, what interferes with cancer treatment, and what is the Achilles heel for cancer-targeted treatment. For NCI, SBDR coordinates leaders in DNA repair (DR) to work together synergistically to provide a comprehensive, mechanistic understanding of DR processes. SBDR removes bottlenecks within individual laboratories and promotes the concerted efforts of multidisciplinary researchers with expertise in different facets of DR. The SBDR Projects and Cores together enable a comprehensive cross-pathway knowledge of dynamic multi- functional DR machines – an understanding that can only be achieved through multi-disciplinary approaches and concerted efforts by multiple groups. The goals of SBDR are 1) to develop structure-based, mechanistic foundation for an actionable understanding of dynamic, multi-functional DR molecular complexes suitable for cancer biology, prognosis, and predispositions, and 2) to enable an integrated quantitative and mechanistic knowledge of DR machines, pathways, and intersections with replication and apoptosis sufficient to aid prediction and intervention for cancer biology by bridging the gaps from mutant sequences to system level correlation. By integrating analyses of major DR and damage response pathways with replication, SBDR will provide detailed and comprehensive information on the maintenance of genetic integrity spanning from specific proteins and complexes to pathways, networks, and signaling. We will apply knowledge-based, determination and integration of structural, biochemical, and biological data on DR protein interactions, modifications, and complexes acting in the five Projects. Our multifaceted structure-based strategy is needed both to dissect multiple activities of multi-functional complexes, such as Mre11-Rad50-Nbs1, and to define how proteins act in multiple pathways. In concert, SBDR Projects and Cores will accomplish four Program Aims: 1) Determine definitive and biologically validated structures of DR complexes, interfaces, & conformations; 2) Dissect the multi-functionality of DR machineries tested by structurally-based examination of separation-of-function mutations and chemical inhibitors; 3) Define crosstalk for DR pathway interactions and delineate and test how DR pathway choice is made; and 4) Discover synthetic lethalities brought about by either mutations or chemical agents that target a specific DR activity that is lethal only in the context of another DR defect to identify and test specific ways to intervene and control biological outcomes to DNA damage for cancer interventions. SBDR will inform cancer biology by providing a comprehensive mechanistic knowledge of how cells respond to DNA damage and how multi-functional DR proteins act in the context of other DNA processes. SBDR will advance understanding of how DR mutations may differentially impact cancer susceptibility and patient risk. SBDR will aid research employing Cancer Genome Atlas mutations and system level correlations as well as consequent therapeutic strategies by providing mechanistic and predictive insights.