The long-term goal of this proposal is to understand, in detail, the molecular mechanisms of telomere length homeostasis through comprehensive biochemical, structural and functional characterizations of the telomeric shelterin complex and its interaction with telomerase. Telomeres ensure genome integrity by facilitating chromosome end replication through telomerase and protect the chromosome ends from DNA repair and degradation activities. Mutations in telomerase subunits or shelterin components have been linked to premature aging and cancer. Shelterin complex and shelterin-telomerase interactions play essential roles in regulating synthesis of telomeric DNA repeats and defining telomere lengths that support or restrict cell proliferation. We will exploit the genetically amendable fission yeast model system and employ a combination of biochemical, high-resolution structural and genetic tools to achieve the following specific aims: 1. Elucidate the biochemical and structural basis of shelterin assembly and its role in telomere length control; 2. Determine the mechanistic basis for telomere switching from the telomerase non-extendible to extendible state; 3. Determine how the activation of non-extendible telomeric state is coupled to telomerase recruitment. Accomplishment of the proposed aims will provide new and significant mechanistic insights into the structure-function relationship and the dynamics of the shelterin complex, and set up the foundation for the development of new therapeutic approaches against diseases caused by telomere dysfunction, such as premature aging.
Telomeres are closely involved in stem cell differentiation and cancer cell proliferation. The results of this study will lead to new mechanistic principles of telomere length regulation and chromosome end protection. Therefore, valuable targets for mechanism- driven design of anti-aging and cancer therapeutics may be identified through this research.
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