Regulation of the DNA damage response by the Mre11 complex

描述(由申请人提供)：在前一个资助期间，获得了关于Mre11复合体细胞周期检查点功能的基本见解。通过阐明Rad50S在DNA损伤信号通路激活中的超形态作用，该复合体作为DNA损伤传感器的作用得到了巩固，并首次表明除了细胞周期检查点外，该复合体还影响细胞凋亡。这里提出的研究计划利用小鼠实验系统来检查对电离辐射的反应以及DNA损伤信号的内在来源。这些研究的一个主要目标是确定ATM调节响应电离辐射和内源性碎裂事件的机制。我们已经建立了Mre11复合体对细胞凋亡、肿瘤抑制和电离辐射诱导的DNA损伤修复的影响在遗传和机械上是可分离的小鼠。这一建议的主要假设是，对DNA损伤的反应是由Mre11复合体将其归类到DNA损伤反应的那些臂中。我们进一步假设，响应的分类是由Mre11复杂的功能相互作用影响的，这些相互作用是特定背景下特有的，例如DNA复制或减数分裂进程。解决这些假设将为理解和改善治疗环境中对电离辐射的反应提供基础。

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.