The MRN complex in Lymphocyte Development and Genome Stability

摘要 细胞对DNA双链断裂的反应需要专业细胞之间的快速沟通。 DNA损伤识别复合物和细胞周期机制的核心，但这种重要的关系 是很难理解的。Mre 11是DNA损伤识别机制的核心组成部分， 在共济失调-毛细血管扩张样疾病（ATLD）中突变，已显示与细胞周期蛋白相互作用 依赖性激酶2（CDK 2），细胞周期机制的核心组成部分。 在本提案中，我们将检验Mre 11与CDK 2相互作用并控制CDK 2的总体假设 以提供正常细胞周期和DNA损伤反应之间的快速切换。我们将 确定Mre 11-CDK 2相互作用在不同的生物学背景中发挥的作用， 淋巴细胞发育中的DNA重组，以及更普遍的S期检查点反应。 本文提出的研究利用先前构建的鼠系统，沿着 新的小鼠品系，模拟人类共济失调毛细血管扩张样疾病。总体而言，拟议的 这些研究将大大有助于我们理解细胞对DNA损伤的反应， 其相关疾病。

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.