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J. Biol. Chem., Vol. 280, Issue 38, 32801-32810, September 23, 2005

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Human Telomerase RNA Template Sequence Is a Determinant of Telomere Repeat Extension Rate^*

From the Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Human telomerase is a specialized reverse transcriptase that utilizes an integral RNA subunit to template the synthesis of telomeres. In the present study, we demonstrate that the human telomerase template sequence not only determines the composition, but also the rate of synthesis, of telomere repeats. Mutagenesis of the template sequence identified variants that reconstitute enzymes with repeat extension rates that were either faster or slower than wild type template. Changes in extension rate could not be attributed solely to altered heteroduplex melting, strongly suggesting that specific interactions between telomerase template, protein, and products contribute significantly in determining repeat extension rate. Furthermore, some substitutions that had no effect on extension rate led to striking increases in repeat processivity, indicating that processivity and extension rates can be regulated independently of each other. Our results suggest that telomerase RNA template sequence is a key determinant of the contribution of telomerase to telomere length regulation.

Received for publication, June 9, 2005 , and in revised form, July 28, 2005.

^* This work was supported by Public Health Service Grants K01-CA87542 (Howard Temin Award to W. C. D.) and R01-AI30861 (to V. R. P.). 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.

¹ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2517; Fax: 718-430-8976; E-mail: prasad{at}aecom.yu.edu.

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