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dc.contributor.authorTomlinson, Rebecca Leah
dc.description.abstractTelomerase is the ribonucleoprotein (RNP) enzyme that synthesizes telomeric repeats at chromosomal termini. Telomerase is inactive in the majority of adult human somatic cells, and the telomeres in these cells grow progressively shorter over an individualÕs lifetime. In contrast, telomerase activity is present in over 90% of cancer cells, and maintenance of telomere length in these cells is critical for their sustained proliferative capacity. Telomerase is thus a promising target for anti-cancer treatments. An understanding of human telomerase regulation would greatly aid in the development of such treatment strategies. Of particular importance is how and where within the cell telomerase is assembled from its component parts and how access of telomerase to telomeres is governed. Here, we present evidence that telomerase accesses to its substrate telomere only during a precise window of the cell cycle and suggest that S phase-specific telomere synthesis is regulated at the level of subnuclear trafficking of the telomerase RNP. The main components of telomerase, telomerase RNA (TR) and telomerase reverse transcriptase (TERT) are housed in separate nuclear foci throughout the majority of the cell cycle. During S phase a dynamic shift in localization of each component occurs. Telomerase transits through two subnuclear structures, Cajal bodies (CBs) and nucleoli, before reaching its functional destination, the telomere. Further, we find that the trafficking of telomerase to CBs and telomeres is closely linked to biogenesis of the enzyme. We also present evidence that CBs serve as sites of telomerase biogenesis. TR localizes to CBs in cells that are telomerase-positive, but not those that are telomerase-negative. Localization of TR to CBs is dependent on TERT expression, and ectopically expressed TERT can be found within CBs. Injection studies in Xenopus oocytes show that TR and TERT are assembled coincident with CB localization of the RNA. However, integration into CBs does not seem to be an important step in the trafficking of telomerase in mouse cells, as mTR is housed within foci separate from CBs throughout the cell cycle. Similar to the occurrences in human cells, mTR is recruited to subsets of telomeres specifically during S phase, making this a potentially useful system to study factors that mediate this recruitment.
dc.subjectTelomerase RNA (TR)
dc.subjectTelomerase Reverse Transcriptase (TERT)
dc.subjectCajal body
dc.subjectIntranuclear trafficking
dc.subjectTelomerase regulation
dc.titleDynamic trafficking of telomerase components
dc.description.advisorMichael Terns
dc.description.committeeMichael Terns
dc.description.committeeWalter Schmidt; Rebecca Terns
dc.description.committeeMichael McEachern
dc.description.committeeSidney Kushner
dc.description.committeeMark Farmer

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