Regulation of the DNA damage response by the Mre11 complex

Mre11 复合物对 DNA 损伤反应的调节

• 批准号: 7737365
• 负责人: John HJ Petrini
• 金额: $ 58.95万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737365
• 关键词: Address; Apoptosis; Cell Cycle Checkpoint; Cherry - dietary; Complex; DNA Damage; DNA biosynthesis; Event; Foundations; Funding; Goals; Ionizing radiation; Manuscripts; Meiosis; Mus; Names; Principal Investigator; Radiation Induced DNA Damage; Regulation; Research; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Source; System; Therapeutic; Time; Tumor Suppression; arm; improved; insight; programs; repaired; response; sensor

DESCRIPTION (provided by applicant): During the previous funding period, fundamental insights regarding the cell cycle checkpoint functions of the Mre11 complex were obtained. The complex's role as a sensor of DNA damage was firmly solidified through the elucidation of Rad50S hypermorphism in activation of the DNA damage signaling pathway, and was shown for the first time to influence apoptosis in addition to cell cycle checkpoints. The research program proposed here utilizes murine experimental systems to examine the response to ionizing radiation as well as intrinsic sources of DNA damage signaling. A major goal of these studies is to define the mechanisms of ATM regulation in response to ionizing radiation and endogenous clastogenic events. We have established mice in which the Mre11 complex's influences on apoptosis, tumor suppression, and the repair of ionizing radiation- induced DNA damage are genetically and mechanistically separable. The governing hypothesis of this proposal is that the response to DNA damage is sorted into those arms of the DNA damage response by the Mre11 complex. We further hypothesize that sorting of the response is effected by Mre11 complex functional interactions that are specific to particular contexts such as DNA replication or meiotic progression. Addressing these hypotheses will provide a foundation for understanding and improving responses to ionizing radiation in therapeutic settings.

描述（由申请人提供）：在上一个资金期间，获得了有关MRE11复合物的细胞周期检查点功能的基本见解。该复合物作为DNA损伤传感器的作用通过在DNA损伤信号途径激活中阐明Rad50S超态性而牢固地巩固，并首次证明除了在细胞周期检查点外，还会影响凋亡。此处提出的研究计划利用鼠实验系统来检查对电离辐射的响应以及DNA损伤信号传导的内在源。这些研究的主要目的是定义ATM调节的机制，以响应电离辐射和内源性层造基因事件。我们已经建立了MRE11复合物对凋亡，肿瘤抑制的影响以及电离辐射诱导的DNA损伤的修复在遗传和机械上可分开的小鼠。该提议的管理假设是，将对DNA损伤的响应分为MRE11复合物的DNA损伤响应的臂。我们进一步假设响应的排序是由MRE11复杂的功能相互作用（例如DNA复制或减数分裂进程）所影响的。解决这些假设将为理解和改善治疗环境中电离辐射的反应提供基础。