Radiation-induced ATM and ERK signaling in DSB repair

DSB 修复中辐射诱导的 ATM 和 ERK 信号传导

基本信息

批准号：
7845000
负责人：
KRISTOFFER Carl VALERIE
金额：
$ 18.63万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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：
2009-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845000
关键词：
ATM Signaling Pathway ATM activation Affect BRCA1 gene Biological Assay Bypass CDC25A gene Cell Cycle Cell Cycle Checkpoint Cell Survival Cell physiology Cells Cellular Stress Cessation of life Critical Pathways DNA Damage DNA Double Strand Break DNA Repair Dominant-Negative Mutation Double Strand Break Repair DsRed Epidermal Growth Factor Receptor Equilibrium Feedback Flow Cytometry Fluorescence Gene Expression Genomics Glioma Growth Growth Factor Growth Factor Receptors Hand Homeostasis Human Human Engineering Ionizing radiation Kinetics Link MEKs Malignant Neoplasms Mammalian Cell Measures Mitogens Monitor Nonhomologous DNA End Joining Nuclear Oxidative Stress PI3K/AKT Participant Pathway interactions Phosphorylation Process Proliferating Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Proto-Oncogene Proteins c-akt Radiation Receptor Signaling Regulation Reporting Role Serine Signal Pathway Signal Transduction Small Interfering RNA Stress System artemis base biological adaptation to stress cancer therapy cell growth design endodeoxyribonuclease SceI homologous recombination improved inhibitor/antagonist interest neoplastic cell novel nuclease public health relevance recombinational repair repaired response

项目摘要

DESCRIPTION (provided by applicant): ATM regulates many cellular processes including DNA damage responses and DNA double-strand break (DSB) repair in addition to responses involving oxidative stress and cell growth. Many of the processes ATM are associated with that are triggered by radiation have been described and characterized. However, the mechanisms involved in ATM's ability to balance growth and assess DNA damage (and other stresses) and help the cell decide between survival and death are relatively unknown. We have recently reported on the interesting observation that in response to radiation, ATM and prosurvival MEK/ERK signaling forms a feedback loop that regulates homologous recombination repair - ATM regulates ERK phosphorylation (and thus activation) whereas MEK/ERK is required for phosphorylation of ATM at serine-1981. Neither mechanism is presently known. Herein, we propose to determine the mechanisms of both these processes as well as the role of ATM and MEK/ERK signaling in regulating non-homologous end-joining (NHEJ), and, in particular, whether ATM and MEK/ERK signaling control DNA repair fidelity in this system. We will focus our studies on finding possible links between growth factor receptor and PI3K/AKT survival signaling and the ability to modulate the quality of NHEJ. A better understanding of these processes is important since there is little information available regarding the cell's ability to balance cellular growth with stress responses in cancer, in particular how it relates to DSB repair. This information might be utilized for improving cancer therapy. PUBLIC HEALTH RELEVANCE: There is little information available regarding the cell's ability to balance cellular growth with stress responses in cancer, in particular how it relates to DNA repair. The dynamic interaction between growth and stress that is controlled by ATM is important and might be utilized for improving cancer therapy.

描述（由申请人提供）：除了涉及氧化应激和细胞生长的反应外，ATM 还调节许多细胞过程，包括 DNA 损伤反应和 DNA 双链断裂 (DSB) 修复。许多与 ATM 相关且由辐射触发的过程已得到描述和表征。然而，ATM 平衡生长、评估 DNA 损伤（和其他应激）以及帮助细胞决定生存和死亡的能力所涉及的机制相对未知。我们最近报道了一个有趣的观察结果，即响应辐射，ATM 和促存活 MEK/ERK 信号传导形成一个调节同源重组修复的反馈环路 - ATM 调节 ERK 磷酸化（从而激活），而 MEK/ERK 是 ATM 磷酸化所必需的在丝氨酸-1981。目前这两种机制尚不清楚。在此，我们建议确定这两个过程的机制以及 ATM 和 MEK/ERK 信号在调节非同源末端连接 (NHEJ) 中的作用，特别是 ATM 和 MEK/ERK 信号是否控制 DNA修复该系统的保真度。我们的研究重点是寻找生长因子受体和 PI3K/AKT 生存信号之间可能的联系以及调节 NHEJ 质量的能力。更好地了解这些过程非常重要，因为关于细胞平衡细胞生长与癌症应激反应的能力的信息很少，特别是它与 DSB 修复的关系。该信息可用于改善癌症治疗。公共健康相关性：关于细胞平衡细胞生长与癌症应激反应的能力，特别是它与 DNA 修复的关系，目前的信息很少。由 ATM 控制的生长和压力之间的动态相互作用非常重要，可用于改善癌症治疗。