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The MRN complex in Lymphocyte Development and Genome Stability

MRN 复合物在淋巴细胞发育和基因组稳定性中的作用

基本信息

批准号：
10266210
负责人：
DAVID O FERGUSON
金额：
$ 60.85万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266210
关键词：
Alleles Ataxia Telangiectasia Biological C-terminal CDK2 gene Cell Cycle Cells Cellular Structures Cerebellar degeneration Communication Complex Congenital Abnormality DNA Damage DNA Double Strand Break DNA Repair Dangerousness Development Developmental Delay Disorders Disease Dissociation Failure G1 Phase Genetic Recombination Genome Stability Hereditary Disease Immunologic Deficiency Syndromes Inherited Investments Ionizing radiation Laboratories Lymphocyte Malignant Neoplasms Malignant lymphoid neoplasm Mediating Mus Mutate Mutation Normal Cell Outcome Pancytopenia Patients Phosphorylation Play Positioning Attribute Predisposition Process Proteins Proteomics Reagent Reporting Research Personnel Role S Phase Structure System Testing Therapeutic Time Transgenic Mice V(D)J Recombination ataxia-telangiectasia like disorder endonuclease human model mouse model multicatalytic endopeptidase complex novel response

项目摘要

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.

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。