Structural Cell Biology of DNA Repair Machines

总括 项目摘要/摘要 DNA修复机器是导致致癌突变的中心，什么是预防癌症，什么是 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)领域的领导者协同工作，以提供全面、 对DR过程的机械性理解。SBDR消除了各个实验室的瓶颈， 促进具有博士不同方面专业知识的多学科研究人员的共同努力 SBDR项目和核心一起实现了对动态多路径的全面了解 功能性灾难恢复机器-只有通过多学科方法才能实现的理解 以及多个团体的共同努力。SBDR的目标是1)开发基于结构的、机械化的 为可操作地理解动态、多功能DR分子络合物奠定了基础 癌症生物学、预后和易感性，以及2)实现综合的量化和机械性 有关DR机器、路径和交叉点的复制和凋亡方面的知识足以帮助 通过从突变序列到系统水平的桥梁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 提供关于保持遗传完整性的详细和全面的信息，范围从特定的 蛋白质和复合体对通路、网络和信号的影响。我们将运用以知识为基础的决心 以及关于DR蛋白相互作用、修饰和结构、生化和生物学数据的集成 在五个项目中发挥作用的综合体。我们基于多方面结构的战略既需要剖析 多功能复合体的多重活性，如Mre11-Rad50-Nbs1，并确定蛋白质如何在 多条小路。SBDR项目和核心将共同实现四个计划目标：1)确定 DR复合体、界面和构象的确定和生物验证结构；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 突变和化学抑制物；3)定义DR途径相互作用的串扰，并描述和测试 DR途径的选择；以及4)发现由突变或 靶向特定DR活性的化学制剂，该活性只有在另一种DR缺陷的情况下才是致命的 确定和测试干预和控制癌症DNA损伤的生物学后果的具体方法 干预措施。SBDR将通过提供全面的机制知识来告知癌症生物学 细胞对DNA损伤做出反应，以及多功能DR蛋白如何在其他DNA过程中发挥作用。 SBDR将促进对DR突变如何不同地影响癌症易感性和 病人风险。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 以及通过提供机械性和预测性见解来制定相应的治疗策略。

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.