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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：
7405997
负责人：
DAVID O FERGUSON
金额：
$ 30.96万
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 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7405997
关键词：
Address Adult Age Alleles Amino Acids Antigen Receptors Apoptosis Asparagine Ataxia Telangiectasia B-Lymphocytes Bacteria Biochemical Biology C-terminal Cell Cycle Cell Cycle Checkpoint Cell Line Cells Cerebellar degeneration Chromatin Chromosomal Breaks Chromosomal Instability Chromosomal translocation Complex Cultured Cells DNA DNA Binding DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA Sequence Rearrangement DNA crosslink DNA repair protein Deoxyribonuclease I Development Developmental Delay Disorders Disease Double Strand Break Repair Embryo Embryonic Development Engineering Event Excision Repair Exons Exonuclease Experimental Models Face Facility Construction Funding Category Failure G2/M Transition Gene Rearrangement Generations Genes Genetic Recombination Genome Stability Genomics Health Histidine Histologic Homologous Gene Human Hypersensitivity Immune system Immunodeficiency and Cancer Immunologic Deficiency Syndromes In Vitro Infertility Inherited Interferons Investigation Ionizing radiation Knowledge Laboratories Learning Length Lymphocyte Mammalian Cell Mammals Meiosis Meiotic Recombination Metabolism Metaphase Spread Molecular Mus Mutate Mutation N-terminal Nerve Degeneration Normal Cell Nucleoplasm Nucleotide Excision Repair Organism Pathway interactions Patients Phase Play Point Mutation Principal Investigator Process Protein Region Proteins Radiation Reagent Relative (related person)Research Personnel Role Site Somatic Mutation Spectral Karyotyping Spermatogenesis Staging Staining method Stains Standards of Weights and Measures System Testing Tissues Transcriptional Regulation Transformed Cell Line Transgenes Yeasts base blastomere structure cell growth ds-DNA embryonic stem cell endonuclease exodeoxyribonuclease in vivo insight member mouse model mutant novel nuclease programs promoter protein function recombinase repaired research study response tumor

项目摘要

DESCRIPTION (provided by applicant): Humans that inherit mutations in the Mre11 gene suffer from extreme sensitivity to ionizing radiation, develop cerebellar degeneration, and have frequent chromosomal translocations in circulating lymphocytes. In addition, somatic mutation of Mre11 has been found in association with various tumors. The Mre11 protein is a member of a complex involved in DNA repair and in the overall cellular responses to DNA damage. 3 proteins comprise this complex; Mre11, Rad50 and NBS. Homologues of Mre11 and Rad50 are conserved from bacteria to metazoans. NBS (XRS2 in yeast) is less well conserved at the amino acid level, but is still required. In vitro biochemical studies and in vivo analyses in yeast have demonstrated that Mre11 possesses single strand DNA endonuclease, single strand DNA exonuclease, and double strand DNA binding activities. The protein is modular in that all nuclease activities are confined to the N terminal region while double strand DNA binding is confined to the C terminus. Much remains to be learned about Mre11 in mammals because studies have been hampered by the cellular lethality of null alleles in common experimental systems, and the realization that ATLD patients harbor mutant alleles that maintain significant protein function. This problem is especially highlighted by the lack of any existing mammalian mutation that inactivates the endo-and exonuclease activities of Mre11 arguably 1 of the most important functions of the Mre11, Rad50, NBS complex. Herein is described the completed construction of the first mouse deficient for the nuclease activities of Mre11. Experiments are proposed which will answer many questions regarding the roles of the highly conserved Mre11 nuclease during normal cell growth, in response to DNA damage, and in specialized recombination events in lymphocytes and gametocytes. These studies may contribute significantly to our understanding of the multifunctional Mre11 protein and its roles in human health and disease.

描述（由申请人提供）：遗传Mre 11基因突变的人类对电离辐射极度敏感，发生小脑变性，循环淋巴细胞中经常发生染色体易位。此外，已发现Mre 11的体细胞突变与多种肿瘤相关。Mre11蛋白是参与DNA修复和对DNA损伤的整体细胞反应的复合物的成员。该复合物由3种蛋白组成：Mre 11、Rad50和NBS。Mre 11和Rad50的同源物从细菌到后生动物都是保守的。NBS（酵母中的XRS2）在氨基酸水平上保守性较差，但仍然是必需的。体外生化研究和酵母体内分析表明，Mre 11具有单链DNA内切酶、单链DNA外切酶和双链DNA结合活性。该蛋白是模块化的，因为所有核酸酶活性被限制在N末端区域，而双链DNA结合被限制在C末端。关于哺乳动物中的Mre 11仍有很多东西需要了解，因为研究受到普通实验系统中无效等位基因的细胞致死性以及ATLD患者携带保持重要蛋白质功能的突变等位基因的认识的阻碍。这个问题特别突出的是缺乏任何现有的哺乳动物突变，失活的内切酶和外切核酸酶活性的Mre 11可以说是一个最重要的功能的Mre 11，Rad50，NBS复合物。本文描述了第一只Mre 11核酸酶活性缺陷小鼠的完整构建。实验提出，这将回答许多问题，高度保守的MRE 11核酸酶在正常细胞生长过程中的作用，在响应DNA损伤，并在专门的重组事件在淋巴细胞和配子体。这些研究可能有助于我们了解多功能Mre11蛋白及其在人类健康和疾病中的作用。