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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：
8269674
负责人：
DAVID O FERGUSON
金额：
$ 38.49万
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 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269674
关键词：
ATM function ATM gene Affect Animal Model Antigen Receptors Ataxia Telangiectasia Ataxia-Telangiectasia-Mutated protein kinase B-Lymphocytes Binding Biochemical Biological Process Cell Cycle Checkpoint Cells Chromosome abnormality Chromosomes Complex Cytosine deaminase DNA DNA Double Strand Break DNA Modification Process DNA Repair DNA Repair Pathway DNA Sequence Rearrangement DNA lesion Defect Deoxyribonucleases Development Developmental Delay Disorders Diagnosis Disease Failure Family Gene Rearrangement Genes Genetic Genome Stability Goals Grant Health Heart Human Immune system Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulin Variable Region Immunologic Deficiency Syndromes Individual Inherited Ionizing radiation Laboratories Lead Learning Lesion Lymphocyte Lymphoid Lymphoma Maintenance Mature B-Lymphocyte Mus Mutate Mutation NBS1 gene Neoplasms Nerve Degeneration Nijmegen Breakage Syndrome Oncogenes Oncogenic Pathologic Pathway interactions Patients Play Predisposition Preparation Process Proteins RNA Splicing Reporting Research Personnel Role Stress Structure Syndrome Systems Development Testing Variant Work ataxia telangiectasia mutated protein cancer therapy cell growth human disease improved in vivo insight leukemia leukemia/lymphoma loss of function mutation mouse model mutant prevent programs public health relevance repaired response

项目摘要

DESCRIPTION (provided by applicant): Several related human diseases result from inherited defects in the ability recognize double strand breaks in DNA and in control of cellular responses to these lesions. These diseases include ataxia telangiectasia, ataxia telangiectasia like disorder, and Nijmegen breakage syndrome which can cause immunodeficiency, predisposition to lymphoma and leukemia, neurodegeneration, and developmental delay. Furthermore, affected individuals are extremely sensitive to ionizing radiation or other stresses that cause double strand breaks, which greatly complicates treatments of cancers that arise. The factors that are mutated in these syndromes are at the heart of the mammalian machinery that detects and repairs DNA double strand breaks. The MRN complex is comprised of Mre11, Rad50 and NBS1. MRN rapidly binds to DNA ends at breaks and plays multiple roles in the preparation for final repair by one of several pathways. While engaging in repair processes, MRN also interacts with and activates the protein kinase ATM, which in turn controls cell cycle checkpoints that prevent cells from dividing until DNA is repaired. The ATM gene is mutated in ataxia telangiectasia, Mre11 in ataxia telangiectasia like disorder, and NBS1 or Rad50 in Nijmegen breakage syndrome. We are continuing our studies to understand how MRN and ATM function, with the ultimate goal of improving the diagnoses and treatment of these diseases. Our approaches include studies of cells and animal models with defects in these genes. Because of the broad impact of these diseases and the diverse roles of the factors involved, this work will also provide important insight into general biological processes required for many aspects of human health and disease. These include the development of our immune system, the maintenance of genomic stability, and control of cellular growth. PUBLIC HEALTH RELEVANCE: Understanding how the MRN complex works will give insight into how our immune system develops and functions. Furthermore, we will learn how cells prevent the DNA rearrangements that occur in the immune system from becoming harmful chromosome aberrations that cause leukemias and lymphomas.

描述（由申请人提供）：几种相关的人类疾病是由于在识别DNA双链断裂和控制细胞对这些病变反应的能力方面的遗传缺陷造成的。这些疾病包括共济失调毛细血管扩张症、共济失调毛细血管扩张样疾病和奈梅亨断裂综合征，后者可导致免疫缺陷、淋巴瘤和白血病易感性、神经变性和发育迟缓。此外，受影响的个体对电离辐射或其他导致双链断裂的压力极其敏感，这大大增加了癌症治疗的复杂性。在这些综合征中发生突变的因子是哺乳动物检测和修复DNA双链断裂机制的核心。MRN复合体由Mre11、Rad50和NBS1组成。MRN在断裂处迅速与DNA末端结合，并通过几种途径之一在最终修复的准备过程中发挥多种作用。在参与修复过程的同时，MRN还与蛋白激酶ATM相互作用并激活，后者反过来控制细胞周期检查点，防止细胞分裂，直到DNA被修复。ATM基因在共济失调性毛细血管扩张症中发生突变，Mre11基因在共济失调性毛细血管扩张样疾病中发生突变，NBS1或Rad50基因在奈梅根断裂综合征中发生突变。我们正在继续研究MRN和ATM的功能，最终目标是改善这些疾病的诊断和治疗。我们的方法包括研究这些基因缺陷的细胞和动物模型。由于这些疾病的广泛影响和所涉及的因素的不同作用，这项工作也将为人类健康和疾病的许多方面所需的一般生物学过程提供重要的见解。这些包括我们免疫系统的发展、基因组稳定性的维持和细胞生长的控制。