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Dissertation/Thesis Abstract

A mechanistic study of POT1-TPP1 mediated human telomerase processivity
by Latrick, Chrysa Marie, Ph.D., University of Colorado at Boulder, 2009, 101; 3366659
Abstract (Summary)

Telomerase contributes to telomere replication by synthesizing repeats of DNA, and two telomeric DNA-binding proteins, POT1 and TPP1, synergistically increase its repeat addition processivity. To study the mechanism of increased processivity, I determined that POT1-TPP1 does not decrease the dissociation rate of telomerase from DNA, prompting reconsideration of the previously proposed sliding and stationary clamp models. Instead, POT1-TPP1 increases the translocation rate and efficiency. A template-mutant telomerase, which synthesizes DNA that cannot be bound by POT1-TPP1, exhibits increased processivity only when at least one POT1-TPP1 binding site is present, evidence for a required POT1-TPP1-DNA interaction during elongation. The effects of POT1-TPP1 are specific as another single-stranded DNA binding protein, gp32, decreases telomerase processivity. POT1-TPP1 stimulates processivity even when substoichiometric relative to the DNA, providing evidence for a recruitment function. I propose a model where POT1-TPP1 must be displaced from the end of a telomere in order for telomerase to initiate, and then, during extension, POT1-TPP1 binds to a nascent telomeric DNA repeat to facilitate the translocation step of repeat addition processivity.

Indexing (document details)
Advisor: Cech, Thomas R.
Commitee: Batey, Robert T., McHenry, Charles S., Pace, Norman R., Wuttke, Deborah S.
School: University of Colorado at Boulder
Department: Chemistry
School Location: United States -- Colorado
Source: DAI-B 70/07, Dissertation Abstracts International
Subjects: Biochemistry
Keywords: POT1, Processivity, TPP1, Telomerase
Publication Number: 3366659
ISBN: 978-1-109-28231-3
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