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The Mre11 complex: linking recombination to checkpoints

Mre11 复合体：将重组与检查点联系起来

基本信息

批准号：
7151945
负责人：
John HJ Petrini
金额：
$ 51.77万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2007-12-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7151945
关键词：
ATM activation Address Affect Antigens Biochemical Genetics Biological Cell Cycle Checkpoint Cells Chromatin Chromosomal Breaks Chromosomal Stability Chromosomes Clinical Complex DNA Damage DNA Repair DNA biosynthesis DNA chemical synthesis Data Defect FHA Domain Female Fertility Foundations Frequencies Funding Genes Genetic Genetic Recombination Genomics Human Link Maintenance Malignant Neoplasms Mediating Medical Surveillance Meiosis Metabolism Metaphase Molecular Mouse Strains Mus Mutation N-terminal NBS1 gene Nomenclature Oogenesis PRKDC gene Pathway interactions Patients Phase Positioning Attribute Proteins Reagent Receptor Gene Regulation Relative (related person)Resolution Role Signal Transduction Sister Chromatid Solid Specific qualifier value Testing Upper arm Yeasts base blastocyst cell injury design genetic analysis genetic resource in vivo insight link protein mutant novel research study response tumorigenesis

项目摘要

In this proposal, we will continue to exploit the mouse strains established in the first funding period to address the mechanisms of the Mre11 complex's actions in chromosome metabolism. In addition, we will test the hypothesis that proteins interacting with the Nbs1 N terminus are critical for regulation of DNA damage responses. We expect that these approaches will continue to provide important insights regarding the role of the Mre11 complex in the maintenance of genomic integrity and the suppression of malignancy. The governing hypothesis of this proposal is that, from its association with chromatin, the Mre11 complex functions as a hub of the DNA damage response. We propose that this association is a prerequisite for its influence on sister chromatid interaction during DSB repair and DNA damage signaling. In addition, we propose that its signaling function takes place via protein interactions that include those governed by the N terminus of Nbs1. We will test these hypotheses through a combination of biochemical and genetic approaches in human cells and mice.

在本提案中，我们将继续利用第一个资助期建立的小鼠品系，以解决Mre 11复合物在染色体代谢中的作用机制。此外，我们将测试的假设，即蛋白质相互作用的Nbs1 N末端的DNA损伤反应的调节是至关重要的。我们希望这些方法将继续提供重要的见解Mre11复合物在维持基因组完整性和抑制恶性肿瘤的作用。该提议的主导假设是，从其与染色质的关联来看，Mre 11复合物作为DNA损伤反应的中心发挥作用。我们认为，这种关联是其影响DSB修复和DNA损伤信号传导过程中姐妹染色单体相互作用的先决条件。此外，我们提出，它的信号传导功能发生通过蛋白质相互作用，包括那些由N末端的Nbs1。我们将通过在人类细胞和小鼠中结合生物化学和遗传学方法来测试这些假设。