The MRN complex in Lymphocyte Development and Genome Stability

摘要 细胞对DNA双链断裂的反应需要在 专门的DNA损伤识别复合体和核心细胞周期机制，但这 人们对重要的关系知之甚少。Mre11，DNA损伤的核心成分 在共济失调-毛细血管扩张样障碍(ATLD)中突变的识别机制已经被 与细胞周期的核心成分--细胞周期蛋白依赖性蛋白依赖性蛋白2(CDK2)相互作用 机械设备。 在这项提案中，我们将测试Mre11与之相互作用并控制这一总体假设 CDK2在正常细胞周期和DNA损伤反应之间提供快速切换。 我们将确定Mre11-CDK2相互作用在不同的生物背景下所扮演的角色 作为淋巴细胞发育中专门的DNA重组，和S阶段检查点 更一般的回应。这里提出的研究利用了以前的 构建小鼠系统，以及模拟人类共济失调的新小鼠品系 毛细血管扩张样疾病。总的来说，拟议的研究将对我们的 了解细胞对DNA损伤及其相关疾病的反应。

Abstract Cellular responses to DNA double strand breaks require rapid communication between specialized DNA damage recognition complexes and the core cell cycle machinery, but this important relationship is poorly understood. Mre11, a core component of the DNA damage recognition machinery that is mutated in ataxia-telangiectasia like disorders (ATLD), has been shown to interact with cyclin dependent kinase 2 (CDK2), a core component of the cell cycle machinery. In this proposal we will test the overarching hypothesis that Mre11 interacts with and controls CDK2 to provide a rapid switch between the normal cell cycle and the DNA damage response. We will determine roles that Mre11-CDK2 interaction plays in diverse biological contexts such as specialized DNA recombination in lymphocyte development, and S phase checkpoint responses more generally. The studies proposed herein take advantage of previously constructed murine systems, along with new mouse lines that model human ataxia telangiectasia-like disorder. Collectively, the proposed studies will significantly contribute to our understanding of cellular responses to DNA damage and their associated diseases.