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.
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.
|Chai, Weihang; Zheng, Li; Shen, Binghui (2013) DNA2, a new player in telomere maintenance and tumor suppression. Cell Cycle 12:1985-6|
|Lin, Weiqiang; Sampathi, Shilpa; Dai, Huifang et al. (2013) Mammalian DNA2 helicase/nuclease cleaves G-quadruplex DNA and is required for telomere integrity. EMBO J 32:1425-39|