A Novel Pathway Involving ATM, PP1 and I-2

涉及 ATM、PP1 和 I-2 的新途径

基本信息

批准号：
8248254
负责人：
Sankar Mitra
金额：
$ 27.17万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8248254
关键词：
ATM function ATM gene Affinity Antibodies Ataxia Telangiectasia Ataxia-Telangiectasia-Mutated protein kinase Binding Carcinogenesis Mechanism Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Death Cell physiology Complex Coupled DNA Damage DNA Repair DNA biosynthesis Data Dissociation Elements Ensure Genotoxic Stress Goals Health Hereditary Disease Human Immunologic Deficiency Syndromes In Vitro Indium Ionizing radiation Lead Light Link Malignant Neoplasms Mammalian Cell Maps Mediating Molecular Pathway interactions Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Play Predisposition Process Protein Serine/Threonine Phosphatase Protein phosphatase Proteins Radiation Induced DNA Damage Radiation Tolerance Recovery Regulation Replication Initiation Role S Phase Sepharose Serine Signal Pathway Signal Transduction Site ataxia telangiectasia mutated protein base cell growth inhibitor/antagonist insight loss of function mutation novel research study response

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal of this project is to elucidate the molecular mechanism of ATM in DNA damage and repair pathways as an attempt to further understand Ataxia Telangiectasia, an autosomal recessive genetic disease associated with loss-of-function mutations in the ATM gene. The ATM protein kinase is considered a critical element in determining cellular responses to ionizing radiation (IR). ATM is activated after DNA damage and signals many key regulators in DNA damage pathways by phosphorylation to initiate an optimal response. Of these, Protein Phosphatase 1 (PP1), a major eukaryotic protein serine/threonine phosphatase that regulates a variety of cellular function in response to DNA damage, is activated in an ATM-dependent manner after IR. However, detailed mechanisms on how ATM activates PP1 remain further explored. We have recently demonstrated that ATM is required for the rapid dissociation of PP1 from its regulatory subunit, Inhibitor-2 (I-2) in response to IR. Furthermore, we found that ATM phosphorylated I-2 at Serine 43 after DNA damage, leading to dissociation of the PP1/I-2 complex and activation of PP1. Our preliminary data in this proposal demonstrated that the ATM/PP1/I-2 pathway was required for the IR-induced S phase and G2/M checkpoints. Further, we found Brca1, Cdc7, and Chk2 presented in a complex with the phosphorylated form of I-2. To dissect the upstream and downstream elements of the ATM/PP1/I-2 pathway and establish links of the pathway to the cell cycle machinery, we propose three specific aims: 1). Investigate the role of Brca1 in ATM-mediated I-2 Ser 43 phosphorylation and PP activation in response to IR; 2) Investigate the role of the ATM/PP1/I-2 pathway on Cdc7 inactivation and the S-phase checkpoint; 3). Investigate the mechanism by which the ATM/PP1/I-2 pathway activates the G2/M checkpoint by studying I-2 mediated Chk2 activation and Chk2 phosphorylation/activation of PP1 in response to IR. Completion of these studies will provide insights into roles and mechanisms of the ATM kinase and, in the process, shed light on general mechanisms involved in the cellular response to DNA damage. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to investigate the functional importance of an ATM- mediated signaling pathway in response to radiation-induced DNA damage as an attempt to further understand the cause of Ataxia-Telangiectasia (A-T), an autosomal recessive genetic disease associated with loss-of-function mutations in the ATM gene.

描述（由申请人提供）：我们该项目的长期目标是阐明 ATM 在 DNA 损伤和修复途径中的分子机制，以进一步了解共济失调毛细血管扩张症，一种与功能丧失相关的常染色体隐性遗传病ATM 基因突变。 ATM 蛋白激酶被认为是决定细胞对电离辐射 (IR) 反应的关键因素。 ATM 在 DNA 损伤后被激活，并通过磷酸化向 DNA 损伤途径中的许多关键调节因子发出信号，以启动最佳反应。其中，蛋白磷酸酶 1 (PP1) 是一种主要的真核蛋白丝氨酸/苏氨酸磷酸酶，可调节多种细胞功能以应对 DNA 损伤，在 IR 后以 ATM 依赖性方式被激活。然而，ATM 如何激活 PP1 的详细机制仍有待进一步探索。我们最近证明，ATM 是 PP1 响应 IR 与其调节亚基 Inhibitor-2 (I-2) 快速解离所必需的。此外，我们发现 DNA 损伤后，ATM 在丝氨酸 43 处磷酸化 I-2，导致 PP1/I-2 复合物解离并激活 PP1。我们在该提案中的初步数据表明，ATM/PP1/I-2 途径是 IR 诱导的 S 期和 G2/M 检查点所必需的。此外，我们发现 Brca1、Cdc7 和 Chk2 与 I-2 的磷酸化形式形成复合物。为了剖析 ATM/PP1/I-2 通路的上游和下游元件并建立该通路与细胞周期机制的联系，我们提出了三个具体目标：1)。研究 Brca1 在 ATM 介导的 I-2 Ser 43 磷酸化和响应 IR 的 PP 激活中的作用； 2）研究ATM/PP1/I-2通路对Cdc7失活和S期检查点的作用； 3）。通过研究 I-2 介导的 Chk2 激活和响应 IR 的 PP1 Chk2 磷酸化/激活，研究 ATM/PP1/I-2 途径激活 G2/M 检查点的机制。这些研究的完成将深入了解 ATM 激酶的作用和机制，并在此过程中揭示细胞对 DNA 损伤反应的一般机制。公共健康相关性：本提案的目的是研究 ATM 介导的信号通路在响应辐射引起的 DNA 损伤中的功能重要性，以进一步了解共济失调毛细血管扩张症 (A-T)（一种常染色体隐性遗传）的病因。与 ATM 基因功能丧失突变相关的疾病。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Strategies for targeting the DNA damage response for cancer therapeutics.

针对癌症治疗的 DNA 损伤反应的策略。

DOI：
发表时间：
2012-08
期刊：
影响因子：
0
作者：
Zhang, Dan;Wang, Hai;Brinkman, Kathryn L;Han, Su;Xu, Bo
通讯作者：
Xu, Bo

New insights into the synergism of nucleoside analogs with radiotherapy.

关于核苷类似物与放疗协同作用的新见解。

DOI：
发表时间：
2013-09-26
期刊：
影响因子：
0
作者：
Lee, Michael W;Parker, William B;Xu, Bo
通讯作者：
Xu, Bo

An essential role for inhibitor-2 regulation of protein phosphatase-1 in synaptic scaling.

抑制剂 2 对蛋白磷酸酶 1 的调节在突触缩放中发挥重要作用。

DOI：
发表时间：
2013-07-03
期刊：
影响因子：
0
作者：
Siddoway, Benjamin A;Altimimi, Haider F;Hou, Hailong;Petralia, Ronald S;Xu, Bo;Stellwagen, David;Xia, Houhui
通讯作者：
Xia, Houhui

The versatile functions of ATM kinase.

ATM 激酶的多功能功能。