Maintenance of the telomere length equilibrium is essential for cell viability. Short telomeres induce a DNA damage response that signals either apoptosis or cellular senescence. In humans, short telomeres limit cell division and play a role in cancer and genetic diseases of tissue renewal such as dyskeratosis congenita and aplastic anemia. To understand the disease pathogenesis associated with short telomeres, we need to have a fundamental understanding of the molecular mechanisms that regulate telomere length. The basic mechanisms of telomere length maintenance are conserved from yeast to humans. We are using the genetically manipulable organism Saccharomyces cerevisiae to study the pathways that regulate telomere length. We recently found that Cdk1 kinase is an important regulator of telomere elongation. We will characterize the pathway and identify substrates that are regulated by Cdk1. We will study how this signaling pathway interacts with other kinase pathways such as the Tel1/Mec1 kinases that also regulate access of telomerase to telomeres. We will characterize how the Tel1 kinase pathway effects chromatin modification that can limit the telomerase access to telomeres. Finally, we will study how these pathways that regulate telomere elongation affect telomere capping, the protective function of telomeres that prevent end-joining and recombination. This work will allow us to identify new regulators of telomere length and understand the mechanisms that establish telomere length homeostasis. This fundamental knowledge can then be applied to human telomeres and may allow new approaches to diagnose and treat human disease. We will use yeast to determine the mechanisms that establish and regulate the telomere length equilibrium. Understanding the molecular pathways in yeast will provide valuable insights into the study of human telomeres and their role in disease.
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