Telomeres are the DNA-protein structures that form the ends of eukaryotic linear chromosomes. Studies from the single-celled organism Saccharomyces cerevisiae have established a negative feedback mechanism that monitors telomere length in vivo. Long telomeres contain more negative regulators that limit further telomere elongation by telomerase, which implies that telomerase preferentially acts on the shortest rather than on all telomeres in the cell. Recently it was shown in S. cerevisiae that not every telomere within a given S-phase is subject to elongation, but occurs in only about 10% of telomeres, with preference for the shortest chromosome ends. This observation suggests that telomere length homeostasis acts by controlling a binary switch between telomerase-extendible and non-extendible states. Our lab have demonstrated that the catalytic subunit of telomerase (Est2p) is telomere-associated throughout most of the cell cycle with peak association occurring in G1 and late S/G2 phases in S. cerevisiae. The telomerase accessory factor, Est1p, is essential for telomere synthesis in vivo, however its role in telomere synthesis in vitro is less clear. The peak telomeric chromatin association of Est1p in vivo coincides with the second peak of Est2p association and with telomere replication late in S/G2 phase, suggesting that Est1p might be a molecular switch controlling telomere length homeostasis. The overall goal of this proposal is to understand how Est1p regulates telomere length homeostasis during replication.
My long-term goal is to understand how telomeres maintain the fidelity and efficiency of DNA replication and its impact on cellular proliferation to maintain genome stability. I would like to continue basic scientific investigations utilizing yeasts and human cells to understand the molecular events that lead to the reactivation of telomerase and consequently telomere length elongation in both normal and aberrant cells. As a member of an underrepresented group in the scientific community (Native Hawaiian), I feel that an academic setting will allow me to better serve as a role model for aspiring young scientists. This training will complement my previous cytological and physiological expertise and will assist me in a career as an independent researcher.
