Function of the ATR-ATRIP Complex

项目摘要/摘要 这项拟议研究的长期目标是了解细胞如何保持基因组的完整性。遗传 不稳定性是癌细胞的一个特征，并解释了它们如何积累多个基因变化 促进肿瘤生长的物质。具有DNA损伤和复制应激反应能力缺陷的细胞 表现出很高的基因组不稳定性。因此，我们的目标是定义DNA的成分 损伤/复制应激反应通路及其协同防癌作用的研究 通过调节细胞周期，促进DNA修复或启动细胞凋亡。ATR(ATM和RAD3相关) 激酶在DNA损伤和复制应激反应通路的顶端发挥作用。在上一次 在资助期间，我们定义了ATR相互作用蛋白(ATIP)促进ATR的几种机制 对基因毒性应激的特殊反应。我们的结果以及其他研究人员的结果表明， ATR信号调节的模型，但许多问题仍然没有答案。我们假设ATR-ATrip 对遗传毒性应激的激活通过多种机制进行调节，包括依赖RPA的机制 定位、TopBP1结合和磷酸化。这一假设将使用以下组合进行检验 生物化学和遗传方法。ATR信号通路的组成部分经常发生突变 几种人类疾病；ATR激活是对最常用的癌症治疗的主要细胞反应； ATR途径有望成为有用的药物靶点。因此，这些机制研究主要集中在 非常重要的生物学问题。项目说明/相关性 DNA损伤反应通路的改变会导致基因组不稳定、神经退行性疾病和 癌症易感性。这些途径调节细胞对许多癌症治疗药物的反应，并且 针对他们的新抗癌药物正在开发中。因此，对DNA如何 损伤反应通路的运行是一个非常重要的研究目标。

Project Summary/Abstract The long-term goal of the proposed research is to understand how cells preserve genomic integrity. Genetic instability is one characteristic of cancer cells and explains how they accumulate multiple genetic alterations that promote tumorigenic growth. Cells with defective DNA damage and replication stress response capabilities exhibit high rates of genomic instability. Therefore, we aim to define the components of DNA damage/replication stress response pathways and determine how they work cooperatively to prevent cancer by regulating the cell cycle, promoting DNA repair or initiating apoptosis. The ATR (ATM and rad3-related) kinase functions at the apex of a DNA damage and replication stress response pathway. In the previous funding period, we defined several mechanisms by which the ATR-interacting protein (ATRIP) promotes ATR specific responses to genotoxic stress. Our results as well as those of other researchers suggest a multi-step model for ATR signaling regulation, but many questions remain unanswered. We hypothesize that ATR-ATRIP activation in response to genotoxic stress is regulated through multiple mechanisms including RPA-dependent localization, TopBP1 binding, and phosphorylation. This hypothesis will be tested using a combination of biochemical and genetic approaches. Components of the ATR signaling pathway are frequently mutated in several human diseases; ATR activation is a major cellular response to most commonly used cancer therapies; and the ATR pathway is expected to be a useful drug target. Therefore, these mechanistic studies focus on highly significant biological questions. Project Narrative/Relevance Alterations in DNA damage response pathways cause genome instability, neurodegenerative disorders, and cancer predisposition. These pathways regulate cellular responses to many cancer therapeutic agents, and new cancer drugs are being developed that target them. Thus, the mechanistic understanding of how DNA damage response pathways operate is a highly significant research objective.