Mechanisms and Functions of ATR signaling

ATR信号传导机制和功能

基本信息

批准号：
10565859
负责人：
David K Cortez
金额：
$ 46.45万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565859
关键词：
Antineoplastic Agents Apical Area Binding Biochemical Cell Cycle Cell Cycle Regulation Cell Survival Cells Chromosome Segregation Clinic Clinical Clinical Trials Complex DNA Damage DNA Repair DNA Repair Inhibition DNA biosynthesis DNA replication fork Data Data Set Defect Dependence Development Dimerization Drug Targeting ETAA1 Excision Exhibits Experimental Genetics Genes Genetic Genetic study Genome Genome Stability Goals Investigation Knowledge Laboratories Link Maintenance Malignant Neoplasms Mass Spectrum Analysis Methods Mitosis Modeling Mutate Mutation Oncogenes Outcome Pathway interactions Pharmaceutical Preparations Phosphotransferases Proliferating Proteins Proteome Proteomics Recycling Regulation Replication Initiation Research Signal Pathway Signal Transduction Surface TOPBP1 Gene TREX1 gene Tertiary Protein Structure Testing Translating Work biological adaptation to stress cancer cell cancer therapy clinical effect expectation genetic approach genome integrity immune checkpoint inhibitor innovation insight loss of function phosphoproteomics premature preservation prevent protein function replication stress response restraint structural biology synergism

项目摘要

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.

项目摘要拟议的研究的长期目标是了解细胞如何保持基因组完整性。具体而言，该应用集中在ATR（ATM和RAD3相关）信号通路上。 ATR功能在 DNA损伤和复制应力响应途径的顶点，每个细胞分裂周期都需要促进基因组的完整而准确的重复。许多癌细胞高度依赖由于致癌基因诱导的复制应力升高，可用于增殖和生存能力的ATR功能和其他基因组维持途径中的突变。因此，ATR可能是基于A的有用药物靶合成致命方法。 ATR抑制剂目前正在各种癌症环境中进行临床试验。我们以前发现，TOPBP1或ETAA1形成了两个独立的ATR信号复合物。在该建议我们研究了这些替代ATR复合物的功能，探索这些蛋白质如何激活ATR，并检查如何根据不同类型的复制挑战来调节ATR。这是一项旨在理解ATR最重要，最了解方面的集中建议功能。使用高级测试基于初步数据的特定假设和创新概念生化和遗传方法。此外，目标为意外发现提供了机会关于维持基因组以及ATR途径抑制剂的机制可能在癌症诊所。