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J. Biol. Chem., Vol. 281, Issue 29, 19840-19848, July 21, 2006

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The Biochemical Role of the Heat Shock Protein 90 Chaperone Complex in Establishing Human Telomerase Activity^*

From the School of Pharmacy, Division of Medicinal Chemistry and Natural Products, University of North Carolina, Chapel Hill, North Carolina 27599-7360

Telomerase is a ribonucleoprotein complex that synthesizes the G-rich DNA found at the 3'-ends of linear chromosomes. Human telomerase consists minimally of a catalytic protein (hTERT) and a template-containing RNA (hTR), although other proteins are involved in regulating telomerase activity in vivo. Several chaperone proteins, including hsp90 and p23, have demonstrable roles in establishing telomerase activity both in vitro and in vivo, and previous reports indicate that hsp90 and p23 are required for the reconstitution of telomerase activity from recombinant hTERT and hTR. Here we report that hTERT and hTR associate in the absence of a functional hsp90-p23 heterocomplex. We also report that hsp90 inhibitors geldanamycin and novobiocin inhibit recombinant telomerase even after telomerase is assembled. Inhibition by geldanamycin could be overcome by allowing telomerase to first bind its primer, suggesting a role for hsp90 in loading telomerase onto the telomere. Inhibition by novobiocin could not similarly be overcome but instead resulted in destabilization of the hTERT polypeptide. We propose that the hsp90-p23 complex fine tunes and stabilizes a functional telomerase structure, allowing primer loading and extension.

Received for publication, October 11, 2005 , and in revised form, May 19, 2006.

^* This work was supported by grants from the North Carolina Pharmacy Foundation and the Elsa U. Pardee Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2.

¹ Fellow of the American Foundation for Pharmaceutical Education.

² Supported by the Medical Alumni Foundation of North Carolina.

³ Supported in part by an R. J. Reynolds Fund Award from the University of North Carolina; an AACP New Faculty award recipient. To whom correspondence should be addressed: School of Pharmacy, Division of Medicinal Chemistry and Natural Products, Campus Box 7360, University of North Carolina, Chapel Hill, NC 27599-7360. Tel.: 919-966-6422; Fax: 919-966-0204; E-mail: jarstfer{at}unc.edu.

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