Mechanisms and Functions of ATR signaling

项目摘要 这项研究的长期目标是了解细胞如何保持基因组的完整性。 具体而言，本申请集中于ATR（ATM和rad3相关）信号通路。ATR功能在 DNA损伤和复制应激反应途径的顶点，这是每个细胞分裂周期所需的， 促进基因组的完整和准确复制。许多癌细胞高度依赖于 由于癌基因诱导的复制应激水平升高，ATR对增殖和生存能力起作用 和其他基因组维持途径中的突变。因此，ATR可以是基于药物靶点的有用的药物靶点。 合成致命方法。ATR抑制剂目前正在各种癌症环境中进行临床试验。我们 先前发现有两个独立的ATR信号复合物由TOPBP1或ETAA1形成。在 这项建议，我们研究这些替代ATR复合物的功能，探索这些蛋白质如何 激活ATR，并检查ATR如何响应不同类型的复制挑战进行调节。这 是一个重点突出的提案，旨在了解ATR最重要和最不了解的方面 功能使用先进的方法测试基于初步数据的具体假设和创新概念 生物化学和遗传学方法。此外，这些目标还为意外的发现提供了机会 关于维持基因组的机制，以及ATR途径抑制剂何时可用于 癌症诊所

Project Summary The long-term goal of the proposed research is to understand how cells preserve genome integrity. Specifically, this application focuses on the ATR (ATM and rad3-related) signaling pathway. ATR functions at the apex of a DNA damage and replication stress response pathway that is needed every cell division cycle to promote the complete and accurate duplication of the genome. Many cancer cells are highly dependent on ATR function for proliferation and viability because of elevated levels of oncogene-induced replication stress and mutations in other genome maintenance pathways. Thus, ATR may be a useful drug target based on a synthetic lethal approach. ATR inhibitors are currently in clinical trials in a variety of cancer settings. We previously found that there are two independent ATR signaling complexes formed by TOPBP1 or ETAA1. In this proposal we examine the functions of these alternative ATR complexes, explore how these proteins activate ATR, and examine how ATR is regulated in response to different types of replication challenges. This is a focused proposal aimed at understanding the most important and least understood aspects of ATR function. Specific hypotheses and innovative concepts based on preliminary data are tested using advanced biochemical and genetic approaches. In addition, the aims provide opportunities for unexpected discoveries about the mechanisms that maintain the genome and when ATR pathway inhibitors may be useful in the cancer clinic.