Clarification of the roles of the telomere binding protein TPP1 and telomerase RNA in telomerase trafficking
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Telomerase is the ribonucleoprotein (RNP) that contains the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TR). It maintains the length of telomeres and is closely associated with aging, cancer, and a few congenital diseases. In humans, the trafficking of telomerase includes the localization of telomerase to Cajal bodies and telomeres. This trafficking process has been shown to be critical in the functioning of telomerase. Our goal is to investigate the factors that affect telomerase trafficking in humans. We tried to clarify the individual roles of the telomere-located shelterin proteins TPP1 and TIN2 in telomerase trafficking. We postulated that TPP1 is the key recruiter for recruitment and we employed a tethering assay using the LacO-lacR system to investigate this hypothesis. We found that TPP1 is the major recruiter in telomerase localization to both telomeres and a non-telomeric site, while TIN2 appears to be expendable. Next, we investigated the molecular basis for the lack of localization of mouse TR to Cajal bodies in mouse cells. We examined the localization of human TR expressed in mouse cells and found that the inherent features of human human TR provide for recruitment of telomerase to Cajal bodies in mice. Taken together, this thesis reveals that telomerase trafficking is a highly regulated process controlled by multiple factors including telomere shelterin proteins and internal telomerase properties.