The Role of Timeless Tipin in Telomere Length Control and Maintenance

Timeless Tipin 在端粒长度控制和维持中的作用

• 批准号: 7806774
• 负责人: Adam Robert Leman
• 金额: $ 2.75万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806774
• 关键词: ATR protein kinase; Address; Age; Aging; Biology; Cell Cycle Checkpoint; Cell Proliferation; Cells; Cessation of life; Chromosomal Breaks; Chromosomes; Complex; DNA; DNA Damage; DNA Sequence; DNA biosynthesis; DNA replication fork; DNA-Directed DNA Polymerase; DNA-Protein Interaction; Ensure; Eukaryotic Cell; Fission Yeast; Functional disorder; Genetic; Genome; Genome Stability; Genomics; Goals; Growth and Development function; Homologous Gene; Human; Investigation; Knowledge; Lead; Length; Maintenance; Mutation; Patients; Phenotype; Play; Premature aging syndrome; Proteins; Recombinant DNA; Repetitive Sequence; Research; Role; Saccharomycetales; Site; Structure; Telomerase; Telomere Length Maintenance; Telomere Maintenance; Telomere Shortening; Travel; Werner Syndrome; Yeasts; human WRN protein; insight; prevent; protein complex; protein structure; recombinational repair; response; telomere; tissue/cell culture

DESCRIPTION (provided by applicant): Telomeres are specialized structures at the end of chromosomes and essential to preserve our DNA that contain genetic information. Telomere shortening and dysfunction are known to accompany human aging. It is also known that patients with premature aging syndromes have abnormally short telomeres. Therefore, our long term goal is to understand how our cells protect telomeres from abnormal shortening to prevent untimely death. Recently, we have shown that two proteins, Timeless and Tipin, form a complex to function as a protector of DNA replication forks, the actual site of DNA synthesis. Our investigations have revealed that in the absence of Timeless or Tipin, replication forks collapse, leading to accumulation of broken chromosomes. Interestingly, yeast species also contain similar proteins to Timeless and Tipin, and their absence causes telomere shortening in yeast cells. Because of significant similarities in telomere maintenance mechanisms between yeast and humans, it is straightforward to suggest that human Timeless and Tipin also control telomere length by regulating replication of telomeres. Therefore, to further understand the mechanism of telomere DNA replication, this application proposes to investigate the roles of Timeless and Tipin in human telomere maintenance mechanism. First, we will determine whether Timeless and Tipin are required for proper length control of human telomeres using mammalian tissue cultured cells. Then, we will investigate how Timeless and Tipin contribute to the efficient replication of telomeric DNA. Since Timeless-Tipin is know to be involved in the DNA damage response that is governed by ATR protein kinase, and ATR is known to be involved in telomere length control, we will also investigate the role of Timeless-Tipin in ATR-dependent telomere maintenance mechanism. This research will determine how Timeless-Tipin promotes efficient replication of telomere DNA to protect the ends of chromosomes. Successful completion of this project will significantly enhance our knowledge of how telomeres are regulated to protect our chromosomes, thereby contributing to the understanding of aging mechanisms.

描述（由申请人提供）：端粒是染色体末端的特殊结构，对于保存包含遗传信息的 DNA 至关重要。众所周知，端粒缩短和功能障碍会伴随人类衰老。人们还知道，早衰综合症患者的端粒异常短。因此，我们的长期目标是了解我们的细胞如何保护端粒免受异常缩短，以防止过早死亡。最近，我们发现两种蛋白质 Timeless 和 Tipin 形成复合物，充当 DNA 复制叉（DNA 合成的实际位点）的保护者。我们的研究表明，在没有 Timeless 或 Tipin 的情况下，复制叉会崩溃，导致断裂染色体的积累。有趣的是，酵母物种也含有与 Timeless 和 Tipin 相似的蛋白质，它们的缺失会导致酵母细胞中的端粒缩短。由于酵母和人类之间的端粒维持机制显着相似，因此很容易表明人类 Timeless 和 Tipin 也通过调节端粒复制来控制端粒长度。因此，为了进一步了解端粒DNA复制的机制，本申请拟研究Timeless和Tipin在人类端粒维持机制中的作用。首先，我们将确定使用哺乳动物组织培养细胞适当控制人类端粒长度是否需要 Timeless 和 Tipin。然后，我们将研究 Timeless 和 Tipin 如何促进端粒 DNA 的有效复制。由于已知 Timeless-Tipin 参与由 ATR 蛋白激酶控制的 DNA 损伤反应，并且已知 ATR 参与端粒长度控制，因此我们还将研究 Timeless-Tipin 在 ATR 依赖性端粒维持中的作用机制。这项研究将确定 Timeless-Tipin 如何促进端粒 DNA 的有效复制以保护染色体末端。该项目的成功完成将显着增强我们对如何调节端粒以保护染色体的知识，从而有助于理解衰老机制。