Defense Date

2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Human Genetics

First Advisor

Shawn Holt

Abstract

The Hsp90 chaperone complex associates with the telomerase enzyme, facilitating the assembly of the ribonucleoprotein complex. While previous data from our laboratory indicate that Hsp90 and p23 remain stably associated with (functionally active) telomerase, more recent experiments suggest that these chaperones associate with telomeres independent of telomerase, presumably through a specific interaction with telomere binding proteins. The current study examines the novel interactions between TRF2, TRF1, TIN2 and TPP1 and molecular chaperones (Hsp90, Hsp70, p23). In vitro and in cell experiments have shown an interaction between TRF1 and TRF2 and the molecular chaperones Hsp90 and Hsp70. Inhibition of Hsp90 using drugs that specifically block ATPase activity results in an increased association of TRF1 and TRF2 with Hsp90 to presumably stabilize the telomere associated proteins to the telomere. A definitive explanation as to the mechanisms underlying the chaperone/telomere associated protein interaction has yet to be determined and further studies examining chaperones’ contribution to telomere structure and function are underway. A better understanding of the telomeric proteins and Hsp90 and their roles in nuclear events is important, as both have extremely important functions in the cell. Our current working hypothesis is that chaperone proteins associate with TRF2, TRF1, TIN2 and TPP1 to facilitate telomeric protein-protein interactions and protein-telomere binding in both cancer and normal cells. The interaction between chaperones and telomere binding proteins may eventually provide a better understanding of telomeric structure and function. Defining the mechanisms of telomeric protein regulation is important in the development of new therapeutic approaches for targeting telomeres to induce dysfunction. Clinical trials are underway employing drugs targeting Hsp90 in cancer cells and given the results here, these Hsp90 compounds likely cause telomere alterations.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2009

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