The MRN complex in Lymphocyte Development and Genome Stability

摘要 细胞对DNA双链断裂的反应需要细胞之间的快速沟通。 专门的DNA损伤识别复合物和核心细胞周期机制，但这 对重要关系了解甚少。Mre 11是DNA损伤的核心成分， 在共济失调-毛细血管扩张样疾病（ATLD）中突变的识别机制， 显示与细胞周期蛋白依赖性激酶2（CDK 2）相互作用，CDK 2是细胞周期的核心成分 机械. 在本提案中，我们将测试Mre 11与Mre 11相互作用并控制Mre 11的总体假设。 CDK 2提供正常细胞周期和DNA损伤反应之间的快速转换。 我们将确定Mre 11-CDK 2相互作用在不同生物学背景中的作用， 作为淋巴细胞发育中的特异性DNA重组， 更一般的回答。本文提出的研究利用以前的 构建了小鼠系统，沿着与新的小鼠品系，模型人类共济失调 毛细血管扩张样疾病总的来说，拟议的研究将大大有助于我们的 了解细胞对DNA损伤的反应及其相关疾病。

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.