Investigation into Mechanisms of CDK1 in Controlling Telomere Stability

CDK1控制端粒稳定性的机制研究

• 批准号: 8445875
• 负责人: Weihang Chai
• 金额: $ 22.65万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445875
• 关键词: Aging; Aging-Related Process; Biochemical; CDC2 Protein Kinase; Cell Aging; Cell Cycle; Cell Cycle Progression; Chromosomes; Complex; DNA; DNA Damage; DNA Repair; DNA Replication Factor; DNA biosynthesis; Data; Development; Disease; Ensure; Foundations; Functional disorder; Future; Genetic Recombination; Genome Stability; Goals; Human body; In Vitro; Individual; Investigation; Knowledge; Lead; Maintenance; Mediating; Outcome; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Premature aging syndrome; Process; Protein Binding; Protein Dynamics; Proteins; Research; Role; Structure; Techniques; Telomere Maintenance; Telomere-Binding Proteins; Testing; Therapeutic; Therapeutic Intervention; Time; Work; anti aging; design; early onset; improved; in vivo; insight; novel; prevent; research study; response; small molecule; telomere

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. PUBLIC HEALTH RELEVANCE: Maintenance of functional telomeres is essential for preserving genome stability and preventing early onset of aging. This proposal aims to yield new insights into studying telomere maintenance mechanism. Findings will assist us in designing more effective therapeutic approaches targeting telomere maintenance to slow down cellular aging.

描述（由申请人提供）：端粒保护染色体末端的完整性，并在细胞和生物衰老中起关键作用。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终端保护并导致不适当的染色体融合或重组，从而触发早期的细胞衰老并减少人体的正常功能。因此，必须了解这些蛋白质在端粒中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重要的蛋白质包括庇护素复合物，DNA修复机制，DNA损伤反应蛋白和DNA复制因子。这些蛋白在进入端粒DNA时的精确协调对于实现功能端粒的维持是必要的。在复制过程中，端粒结合蛋白可以访问端粒DNA，此时端粒结构会发生动态变化，端粒DNA可以访问各种蛋白质。但是，对这些蛋白质如何访问端粒DNA的基本机制以及它们如何彼此合作以实现端粒保护的方式知之甚少。在我们最近的工作中，我们证明了Cyclin依赖性激酶1（CDK1）是控制细胞周期进程的关键激酶，在调节调节中起着至关重要的作用 端粒的结构变化和维持端粒不稳定性。我们对该建议的中心假设是CDK1可以调节细胞周期中端粒的动态结构变化，并控制端粒结合蛋白对端粒DNA的访问。我们将在以下两个目标中检验这一假设。 AIM 1，确定端粒上的CDK1磷酸化靶标。 AIM 2，表征蛋白质组成在细胞周期期间铅和滞后端粒的动力学，并分析CDK1抑制对端粒蛋白质组成的影响。这些研究的发现将提高我们对维持端粒完整性和基因组稳定性机制的理解，因此，可以避免与功能障碍端粒诱导的早衰相关的疾病。 公共卫生相关性：维持功能端粒对于保持基因组稳定性和防止早期衰老的发作至关重要。该提案旨在为研究端粒维护机制提供新的见解。发现将有助于我们设计针对端粒维持的更有效的治疗方法，以减慢细胞衰老。