Regulation of the ATR Checkpoint Kinase by DNA Damage

DNA 损伤对 ATR 检查点激酶的调节

基本信息

批准号：
8523909
负责人：
Lee Zou
金额：
$ 31.57万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-25 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523909
关键词：
Address Biochemical Biological Biological Assay Biological Process Cell Cycle Progression Cell division Cell physiology Cells Checkpoint kinase 1 Complex DNA Damage DNA Double Strand Break DNA Repair DNA Structure DNA biosynthesis DNA damage checkpoint Defect Development Developmental Cell Biology Disease Event Future Genetic Genome Genome Stability Genomic Instability Genotoxic Stress Goals Human In Vitro Lead Link Malignant Neoplasms Modeling Modification Molecular Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphorylation Site Phosphotransferases Play Premature aging syndrome Process Proteins Proteomics Radiation Recovery Regulation Role Signal Pathway Signal Transduction Site Staging System TREX1 gene ataxia telangiectasia mutated protein base cancer cell cancer therapy human disease novel novel therapeutics response sensor treatment strategy tumor progression

项目摘要

DESCRIPTION (provided by applicant): How genomic stability is maintained during cell divisions and development is a fundamental question for Cell and Developmental Biology with a strong implication in human diseases including cancer. To maintain a stable genome, cells rely on the concerted action of several cellular processes, including faithful DNA replication, efficient DNA repair, and coordinated cell cycle progression. The DNA damage-signaling pathway, also known as the DNA damage checkpoint, is the central conductor of these processes. The ataxia-telangiectasia mutated and rad3-related (ATR) checkpoint kinase is a master regulator of the checkpoint pathway. As the main cellular sensor of a broad spectrum of DNA damage and genomic instability, ATR plays a key role in protecting the genome, particularly during DNA replication. Compromised ATR signaling increases genomic instability, contributing to the development and progression of cancer. Furthermore, ATR is activated by radiation and many chemotherapeutic drugs, and defective ATR response renders cancer cells highly sensitive to extrinsic and intrinsic DNA damage. Given the pivotal role of ATR in DNA damage response and cancer therapy, it is of great importance to understand the molecular mechanisms by which ATR is activated and by which it functions. A better understanding of the regulation and function of ATR will be critical for the development of new cancer therapies to target the genomic instability in cancer cells. Our main goal in this proposal is to understand how ATR is transformed into a fully active kinase during DNA damage response. Furthermore, we will investigate how the ATR- Chk1 signaling pathway is activated during the early stage of DNA damage response, and how it is deactivated at the late stage of the response. Our studies will combine biochemical, cell biological, and proteomic approaches. In particular, we will analyze how ATR and its regulators and effectors are modified after DNA damage, and how these modifications regulate their functions. We will also systematically develop an in vitro biochemical assay system to recapitulate the activation of ATR by DNA damage. These studies will allow us to clearly define the key molecular events that lead to ATR activation, as well as the key events that orchestrate the signaling through the ATR-Chk1 pathway. These studies may significantly advance the current model of ATR activation, providing the molecular basis for future studies to reveal the full biological functions of ATR and its implications in targeted cancer therapy.

描述（由申请人提供）：在细胞分裂和发育过程中如何维持基因组稳定性是细胞和发育生物学的一个基本问题，对包括癌症在内的人类疾病具有强烈的影响。为了维持稳定的基因组，细胞依赖于多个细胞过程的协同作用，包括忠实的 DNA 复制、有效的 DNA 修复和协调的细胞周期进程。 DNA 损伤信号通路，也称为 DNA 损伤检查点，是这些过程的中心导体。共济失调毛细血管扩张突变和 rad3 相关 (ATR) 检查点激酶是检查点通路的主要调节因子。作为广泛 DNA 损伤和基因组不稳定性的主要细胞传感器，ATR 在保护基因组方面发挥着关键作用，特别是在 DNA 复制过程中。 ATR 信号传导受损会增加基因组的不稳定性，从而导致癌症的发生和进展。此外，ATR 被辐射和许多化疗药物激活，并且有缺陷的 ATR 反应使癌细胞对外在和内在 DNA 损伤高度敏感。鉴于 ATR 在 DNA 损伤反应和癌症治疗中的关键作用，了解 ATR 激活及其发挥作用的分子机制非常重要。更好地了解 ATR 的调节和功能对于开发针对癌细胞基因组不稳定性的新癌症疗法至关重要。我们本提案的主要目标是了解 ATR 在 DNA 损伤反应过程中如何转化为完全活跃的激酶。此外，我们将研究ATR-Chk1信号通路如何在DNA损伤反应的早期阶段被激活，以及它如何在反应的后期阶段失活。我们的研究将结合生物化学、细胞生物学和蛋白质组学方法。特别是，我们将分析ATR及其调节子和效应子在DNA损伤后如何被修饰，以及这些修饰如何调节它们的功能。我们还将系统地开发体外生化检测系统，以概括 DNA 损伤对 ATR 的激活作用。这些研究将使我们能够清楚地定义导致 ATR 激活的关键分子事件，以及通过 ATR-Chk1 途径协调信号传导的关键事件。这些研究可能会显着推进当前的 ATR 激活模型，为未来研究揭示 ATR 的全部生物学功能及其在癌症靶向治疗中的影响提供分子基础。