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Function and Dynamics of Tetrahymena Telomere Proteins

四膜虫端粒蛋白的功能和动态

基本信息

批准号：
8300897
负责人：
Carolyn M Price
金额：
$ 30.78万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300897
关键词：
Address Affect Affinity Binding Biochemical Biochemistry Cell Cycle Cell Cycle Regulation Cells Chromatin Chromosomal Breaks Chromosome Breakage Chromosomes Complex DNA DNA Damage DNA Repair DNA Sequence DNA Sequence Rearrangement DNA Structure DNA-Directed DNA Polymerase Defect Development Digestion Dyskeratosis Congenita Ensure Enzymes Exhibits Family member Genes Genetic Global Change Goals Growth Healed Health Hereditary Disease Homologous Gene Human Individual Knock-out Label Lead Length Malignant Neoplasms Mass Spectrum Analysis Monitor Nature Organism Outcome Oxytricha Partner in relationship Phenotype Play Process Proteins Pulmonary Fibrosis Recombinant DNA Recruitment Activity Regulation Research Role S Phase Site Specificity Structure Telomerase Telomere Capping Telomere Shortening Testing Tetrahymena Transferase Western Blotting Work chromosome replication healing human disease novel nuclease prevent programs protein complex protein function telomere trait

项目摘要

The overall goal of this research is to understand how telomere proteins regulate telomerase recruitment and other the steps in telomere replication, but yet ensure that the chromosome terminus is protected from unwanted DNA repair or processing activities during the remainder of the cell cycle. The research is pertinent to human health because loss of telomere capping leads to chromosome fusions and chromosome rearrangements, the underlying cause of many forms of cancer. Defects in telomerase action are also associated with human disease as the resulting telomere shortening can lead to dyskeratosis congenita and pulmonary fibrosis. Telomere protection is generally achieved by multi-protein complexes that bind the telomeric DNA and sequester the DNA terminus. During replication, some of the same proteins regulate processing of the telomeric DNA, recruit telomerase, or stimulate telomerase activity. However, the mechanism by which individual proteins regulate these processes is still poorly understood. We will address this question through aims 1 and 3 which examine how three newly identified Tetrahymena telomere proteins, p61, p45 and Pot1b, regulate access to telomerase, enhance telomerase activity, or promote new telomere synthesis. Aim 2 addresses the dynamic nature of telomere structure. Telomeres must undergo a structural switch during S-phase in order to make the chromosome terminus accessible. Despite the importance of this structural change, the underlying cause is not understood. We will tackle this problem by examining Tetrahymena telomere composition and how this changes during the cell cycle or under different growth conditions. We will use Tetrahymena for our work because it has unique traits that make it exceptionally well suited for the genetic and biochemical approaches needed to address the above questions. In particular, it has ~40,000 telomeres per cell, correspondingly high levels of telomerase, and telomeres that exist as discrete complexes which can be purified from bulk chromatin. The specific aims are as follows. Aim 1: Determine the function of p61 and p45 in telomere capping and telomerase regulation. Aim 2: Characterize Tetrahymena telomere composition and dynamics. Aim 3: Determine the role of Pot1b during new telomere synthesis. The outcome should be a comprehensive picture of the role played by individual telomere proteins in telomere protection, replication, and chromosome healing, and of how the dynamic changes in telomere organization promote these processes.

本研究的总体目标是了解端粒蛋白如何调节端粒酶的募集