Investigation into Mechanisms of CDK1 in Controlling Telomere Stability

描述（申请人提供）：端粒保护染色体末端的完整性，并在细胞和生物体老化中发挥关键作用。端粒的保护功能是通过多个端粒结合蛋白的协同作用来实现的。这些蛋白质的缺乏损害染色体末端保护，导致不适当的染色体融合或重组，引发早期细胞衰老和降低人体的正常功能。因此，有必要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。维持端粒稳定性的重要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。在这些蛋白质接近端粒DNA时，它们之间的精确协调对于实现端粒功能的维持是必要的。端粒结合蛋白在复制过程中获取端粒DNA，端粒结构在复制过程中发生动态变化，端粒DNA可以被多种蛋白获取。然而，调节这些蛋白质如何进入端粒DNA以及它们如何相互协作以实现端粒保护的潜在机制尚不清楚。在我们最近的工作中，我们已经证明了周期蛋白依赖性激酶1 (CDK1)，一个控制细胞周期进程的关键激酶，在调节细胞凋亡中起着至关重要的作用

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.