Regulation of the DNA damage response by the Mre11 complex

描述（由申请人提供）：在之前的资助期内，获得了关于Mre11复合物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态性，该复合体作为DNA损伤传感器的作用得到了巩固，并且首次显示除了细胞周期检查点外，该复合体还影响凋亡。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在电离辐射和内源性破胚事件下的调节机制。我们已经建立了Mre11复合物对细胞凋亡、肿瘤抑制和电离辐射诱导的DNA损伤修复的影响是遗传上和机制上可分离的小鼠。这一提议的主导假设是，对DNA损伤的反应被Mre11复合体分成了DNA损伤反应的那些部分。我们进一步假设，反应的排序受到Mre11复杂功能相互作用的影响，这些相互作用对特定环境（如DNA复制或减数分裂过程）具有特异性。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.