Mechanisms of ATM activation by the MRN complex and DNA Double Strand Breaks

项目摘要 DNA双链断裂（DSB）是一种主要由电离辐射引起的灾难性事件 这可能导致突变、染色体重排、基因组不稳定，最终导致癌症。所述MRN 蛋白质复合物和ATM激酶是参与感测DSB和启动细胞凋亡的核心参与者。 这是一种导致损伤修复、凋亡或衰老的反应。尽管其重要性众所周知， DSB传感和修复，关于MRN如何在DSB上组装，ATP驱动如何在DSB上组装， MRN的构象变化有助于DSB修复，以及MRN如何募集和激活ATM激酶。这 一项提案寻求利用最先进的低温电子显微镜（cryo-EM）技术，沿着 严格的生化分析，以获得高分辨率的结构和功能的见解，这些关键 流程.这些研究将提供对这一途径的更全面的理解，并将为 未来的结构导向药物设计工作的方式，针对MRN：ATM相互作用在癌细胞中。 !

Project Summary DNA double stranded breaks (DSBs) are catastrophic events caused mainly by exposure to ionizing radiation that can lead to mutations, chromosomal rearrangements, genome instability, and ultimately cancer. The MRN protein complex and ATM kinase are central players involved in sensing a DSB and initiating a cellular response that leads to either repair of the lesion, apoptosis, or senescence. Despite their known importance in DSB sensing and repair, little is understood regarding how MRN assembles on DSBs, how ATP-driven conformational changes in MRN aid in DSB repair, and how MRN recruits and activates ATM kinase. This proposal seeks to utilize state-of-the-art cryogenic electron microscopy (cryo-EM) techniques, along with rigorous biochemical assays to gain high-resolution structural and function insights into these key processes. These studies will provide both a more complete understanding of this pathway, and will pave the way for future structure guided drug design efforts targeting the MRN:ATM interaction in cancer cells. !