Investigation into Mechanisms of CDK1 in Controlling Telomere Stability

CDK1控制端粒稳定性的机制研究

基本信息

批准号：
8554749
负责人：
Weihang Chai
金额：
$ 17.84万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2015-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Telomeres protect the integrity of chromosome ends and play a key role in cellular and organismal aging. The protective function of telomeres is achieved by coordinated actions of multiple telomere-binding proteins. Deficiencies in these proteins impair chromosome end protection and lead to inappropriate chromosome fusions or recombination, triggering early cellular senescence and diminishing normal functions of a human body. It is therefore imperative to understand the roles of these proteins at telomeres and the consequences of dysfunction of these proteins. Proteins important for maintaining telomere stability include shelterin complex, DNA repair machinery, DNA damage response proteins, and DNA replication factors. Precise coordination between these proteins upon their access to telomeric DNA is necessary to achieve the maintenance of functional telomeres. Telomere-binding proteins gain access to telomeric DNA during replication, at which time telomere structure undergoes dynamic changes and telomeric DNA becomes accessible to various proteins. However, the underlying mechanisms regulating how these proteins access telomeric DNA and how they collaborate with each other to achieve telomere protection are poorly understood. In our recent work, we have demonstrated that cyclin-dependent kinase 1 (CDK1), a key kinase controlling the cell cycle progression, plays a crucial role in regulating the structural changes at telomeres and in maintaining telomere instability. Our central hypothesis for this proposal is that CDK1 may regulate the dynamic structural changes of telomeres during the cell cycle and also control the access of telomere-binding proteins to telomeric DNA. We will test this hypothesis in the following two aims. Aim 1, Determine CDK1 phosphorylation targets at telomeres. Aim 2, Characterize the dynamics of protein composition at leading and lagging telomeres during the cell cycle and analyze the effects of CDK1 inhibition on protein composition at telomeres. The findings from these studies will advance our understanding in the mechanism for maintaining telomere integrity and genome stability, and therefore, the diseases associated with dysfunctional telomeres induced premature aging can be avoided.

描述（由申请人提供）：端粒保护染色体末端的完整性，并在细胞和有机体衰老中发挥关键作用。端粒的保护功能是通过多种端粒结合蛋白的协调作用来实现的。这些蛋白质的缺陷会损害染色体末端保护并导致不适当的染色体融合或重组，引发早期细胞衰老并削弱人体的正常功能。因此，必须了解这些蛋白质在端粒上的作用以及这些蛋白质功能障碍的后果。对于维持端粒稳定性很重要的蛋白质包括庇护蛋白复合物、DNA 修复机制、DNA 损伤反应蛋白和 DNA 复制因子。这些蛋白质在接触端粒 DNA 时的精确协调对于实现功能性端粒的维持是必要的。端粒结合蛋白在复制过程中接触到端粒 DNA，此时端粒结构发生动态变化，端粒 DNA 变得可以接触到各种蛋白质。然而，人们对调节这些蛋白质如何获取端粒 DNA 以及它们如何相互协作以实现端粒保护的潜在机制知之甚少。在我们最近的工作中，我们证明了细胞周期蛋白依赖性激酶 1 (CDK1)，一种控制细胞周期进程的关键激酶，在调节细胞周期中发挥着至关重要的作用。端粒的结构变化和维持端粒的不稳定性。我们对该提议的中心假设是，CDK1 可能在细胞周期中调节端粒的动态结构变化，并控制端粒结合蛋白与端粒 DNA 的接触。我们将在以下两个目标中检验这一假设。目标 1，确定端粒处的 CDK1 磷酸化靶点。目标 2，表征细胞周期中超前端粒和滞后端粒蛋白质组成的动态，并分析 CDK1 抑制对端粒蛋白质组成的影响。这些研究的结果将增进我们对维持端粒完整性和基因组稳定性机制的理解，因此，可以避免与端粒功能失调引起的过早衰老相关的疾病。