Eukaryotic Telomere Dynamics

真核端粒动力学

基本信息

批准号：
7627889
负责人：
Arthur J. Lustig
金额：
$ 0.76万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7627889
关键词：
Address Age Alleles Behavior Biological Models Bypass Cell Cycle Regulation Cell Survival Cells Chromosomes Class Complex Condition Cultured Cells DNA Structure Data Defect Dissection Employee Strikes Eukaryota Eukaryotic Cell Facility Construction Funding Category Genetic Recombination Goals Homeostasis Homologous Gene Length Light Link Maintenance Mediating Medical Meiosis Methods Mitosis Mitotic Modeling Mutation Nature Pathway interactions Phenotype Physiological Process Proteins Rate Regulation Role Saccharomyces cerevisiae Structure Surveys Telomerase Telomere Recombination Tertiary Protein Structure Testing Vertebrates Work Yeasts falls gain of function human tissue interest novel prevent senescence size stem telomere tissue culture tool tumorigenesis

Address Age Alleles Behavior Biological Models Bypass Cell Cycle Regulation Cell Survival Cells Chromosomes Class Complex Condition Cultured Cells DNA Structure Data Defect Dissection Employee Strikes Eukaryota Eukaryotic Cell Facility Construction Funding Category Genetic Recombination Goals Homeostasis Homologous Gene Length Light Link Maintenance Mediating Medical Meiosis Methods Mitosis Mitotic Modeling Mutation Nature Pathway interactions Phenotype Physiological Process Proteins Rate Regulation Role Saccharomyces cerevisiae Structure Surveys Telomerase Telomere Recombination Tertiary Protein Structure Testing Vertebrates Work Yeasts falls gain of function human tissue interest novel prevent senescence size stem telomere tissue culture tool tumorigenesis

展开

项目摘要

Telomeres, the specialized protein-DNA structures present at the chromosomal terminus serve as 'caps' to prevent deleterious processes that would result in toss of linear chromosomes. The maintenance of an appropriate length of telomedc simple sequences to provide cap function is therefore essential for cell viability. Indeed, defects in telomere size control have been linked with both aging and oncogenesis. We have been studying the mechanism of size control in the yeast Saccharomyces cerevisiae as a model system. The basic outline of telomere size control is remarkably similar in yeast and vertebrates. Hence, the construction of a model system that can be easily manipulated gives us the opportunity to provide the framework for higher eukaryotic functional homologs. Previous studies have uncovered a process termed telomeric rapid deletion (TRD) that excises over-elongated telomere tracts to wild type sizes by a recombination mechanism. Two components regulate this process: the mechanism for the deletion process, and the mechanism of sizing among telomeres that governs the precision of deletion. The major goal in this proposal is to understand the mechanism of TRD. Three aims will be pursued. The first aim is the characterization of the cell cycle control of TRD and the characterization of meiotic TRD which displays dramatically increased rates of TRD. The only protein known to be essential for TRD is the recombination protein Mrel 1. The second aim is to study the essential role of Mrel 1 in TRD through the extensive characterization of a battery of missense alleles falling within unique domains of the protein The third aim examines an unusual allele of Mrel 1, A470T, that confers two major phenotypes, a loss of TRD precision and an ability to bypass senescence conferred by a loss of telomerase. Specific hypotheses f or the function of Mrel 1 in checkpoint control on telomere processing are tested using the tools made available from preliminary data. Proteins that interact with the motif surrounding A470T will be sought through the use of the Tap-tag method of isolating soluble native complexes.

端粒，染色体末端存在的专门蛋白-DNA结构可作为“帽” 有害过程将导致线性染色体折腾。维护适当的长度因此，提供CAP功能的telomedc简单序列对于细胞活力至关重要。确实，端粒缺陷尺寸控制已与衰老和肿瘤发生有关。我们一直在研究尺寸控制的机制在酿酒酵母的酵母菌中，作为模型系统。端粒尺寸控制的基本轮廓非常明显酵母和脊椎动物类似。因此，可以轻松操纵的模型系统的构建为我们提供了为高级真核功能同源物提供框架的机会。先前的研究发现了一种称为端粒快速删除（TRD）的过程，该过程对过度估算通过重组机制将端粒量变为野生型的大小。两个组件调节了此过程：删除过程的机制，以及控制精度的端粒之间的大小机制删除。该提案的主要目标是了解TRD的机制。将追求三个目标。第一个目标是TRD的细胞周期控制的表征以及显示的减数分裂TRD的表征 TRD的速率急剧增加。唯一已知对于TRD必不可少的蛋白质是重组蛋白 MREL 1。第二个目的是通过广泛的表征研究MREL 1在TRD中的重要作用第三个目的属于蛋白质的独特域内的电池电池等位基因检查的异常等位基因 MREL 1，A470T，赋予了两种主要表型，TRD精度的损失和绕过衰老的能力由端粒酶的损失赋予。特定的假设f或MREL 1在端粒检查点控制中的功能使用初步数据提供的工具对处理进行测试。与基序相互作用的蛋白质通过使用TAP-TAG方法来隔离可溶性天然复合物，将寻求周围的A470T。