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人员之间的快速沟通 DNA损伤识别复合体和核心细胞周期机制，但这一重要关系 人们对此知之甚少。Mre11，DNA损伤识别机制的核心组件，即 共济失调-毛细血管扩张样病(ATLD)中的突变已被证明与细胞周期蛋白相互作用 依赖性激酶2(CDK2)，细胞周期机制的核心组成部分。 在这个提案中，我们将测试Mre11与CDK2相互作用并控制CDK2的主要假设 在正常细胞周期和DNA损伤反应之间提供快速切换。我们会 确定Mre11-CDK2相互作用在不同的生物学环境中所扮演的角色 DNA重组在淋巴细胞发育和S时相检查点反应中较为普遍。 这里提出的研究利用了以前构建的小鼠系统，以及 模拟人类共济失调毛细血管扩张样疾病的新小鼠品系。总的来说，建议的 研究将大大有助于我们理解细胞对DNA损伤的反应和 他们的相关疾病。

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.