权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Roles of Mre11 in Lymphocyte Development and DNA Repair

Mre11 在淋巴细胞发育和 DNA 修复中的作用

基本信息

批准号：
9026905
负责人：
DAVID O FERGUSON
金额：
$ 37.58万
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：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9026905
关键词：
Age Alleles Ataxia Telangiectasia Biological CDK2 gene Cell Cycle Cell Cycle Checkpoint Cell Line Cells Cerebellar degeneration Clinical Communication Complex Congenital Abnormality Core Protein DNA DNA Damage DNA Double Strand Break DNA Repair DNA damage checkpoint Defect Development Developmental Delay Disorders Disease Disease Progression Dissociation Event Failure G1 Phase General Population Generations Genetic Recombination Immune Immunologic Deficiency Syndromes Inborn Genetic Diseases Individual Inherited Investigation Investments Laboratories Left Lymphocyte Malignant Neoplasms Malignant lymphoid neoplasm Mammalian Cell Mediating Mus Mutate Mutation Normal Cell Outcome Pancytopenia Patients Phosphorylation Play Positioning Attribute Predisposition Process Proteins Reagent Reporting Research Personnel Role S Phase System Testing Time V(D)J Recombination ataxia telangiectasia mutated protein ataxia-telangiectasia like disorder base endonuclease leukemia/lymphoma mouse model multicatalytic endopeptidase complex mutant novel therapeutics programs public health relevance repaired response

项目摘要

DESCRIPTION (provided by applicant): Inherited disorders resulting from defective responses to DNA double strand breaks feature immunodeficiency, bone marrow failure, lymphoid malignancies and developmental delay. Cellular responses to 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. In the previous project period we identified an unanticipated protein interaction that provides a unique opportunity to make major strides in understanding this relationship. The interaction involves Mre11, a core component of the DNA damage recognition machinery that is mutated in ataxia-telangiectasia like disorders (ATLD), and cyclin dependent kinase 2 (CDK2), a core component of the cell cycle machinery. We reported that the interaction facilitates CDK2 dependent phosphorylation of a single substrate, demonstrating for the first time that Mre11 has roles in the normal cell cycle. In this proposal we present preliminary evidence that Mre11 controls CDK2 functions more globally during the normal cell cycle. Our findings indicate that this control plays an important role when cells undergo DNA damage. Therefore, 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 is diverse biological contexts such as specialized recombination in lymphocyte development, and S phase checkpoint responses more generally. The studies proposed herein take advantage of murine systems with alleles of Mre11 that we constructed in the previous two project periods, along with new mouse models we will develop to directly test our hypotheses. The combination of our long term investment in the development of unique biological reagents and our discovery of Mre11-CDK2 interaction places the Principle Investigator's laboratory in a unique position to make major strides in our understanding of cellular responses to DNA damage and their associated diseases.

描述（由申请方提供）：由DNA双链断裂反应缺陷引起的遗传性疾病，特征为免疫缺陷、骨髓衰竭、淋巴恶性肿瘤和发育迟缓。细胞对双链断裂的反应需要专门的DNA损伤识别复合物和核心细胞周期机制之间的快速通信，但这种重要的关系知之甚少。在上一个项目中在此期间，我们发现了一种意想不到的蛋白质相互作用，这为理解这种关系提供了一个独特的机会。这种相互作用涉及Mre 11和细胞周期蛋白依赖性激酶2（CDK 2），Mre 11是共济失调-毛细血管扩张样疾病（ATLD）中突变的DNA损伤识别机制的核心组分，CDK 2是细胞周期机制的核心组分。我们报道了这种相互作用促进了CDK 2依赖的单一底物磷酸化，首次证明了Mre 11在正常细胞周期中的作用。在这项提案中，我们提出了初步的证据，Mre 11控制CDK 2的功能更全面的正常细胞周期。我们的研究结果表明，当细胞发生DNA损伤时，这种控制起着重要作用。因此，我们将测试总体假设，即Mre 11与CDK 2相互作用并控制CDK 2，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下发挥的作用，例如淋巴细胞发育中的专门重组，以及更普遍的S期检查点反应。本文提出的研究利用了我们在前两个项目期间构建的具有Mre 11等位基因的小鼠系统，沿着我们将开发新的小鼠模型来直接测试我们的假设。我们在开发独特的生物试剂方面的长期投资和我们对Mre 11-CDK 2相互作用的发现相结合，使主要研究者的实验室处于一个独特的位置，在我们对DNA损伤及其相关疾病的细胞反应的理解方面取得了重大进展。