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J. Biol. Chem., Vol. 280, Issue 28, 26586-26591, July 15, 2005

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A Physical and Functional Constituent of Telomerase Anchor Site^*

Neal F. Lue

From the Department of Microbiology and Immunology, W. R. Hearst Microbiology Research Center, Weill Medical College of Cornell University, New York, New York 10021

Telomerase is a ribonucleoprotein reverse transcriptase responsible for the maintenance of one strand of the telomere terminal repeats. It consists minimally of a catalytic protein component (TERT) and an RNA subunit that provides the template. Compared with prototypical reverse transcriptases, telomerase is unique in possessing a DNA binding domain (anchor site) that is distinct from the catalytic site. Yeast TERT mutants bearing deletion or point mutations in an N-terminal domain (known as N-GQ) were found to be selectively impaired in extending primers that form short hybrids with telomerase RNA. The mutants also suffered a significant loss of repeat addition processivity but displayed an enhancement in nucleotide addition processivity. Furthermore, the mutants manifested altered primer utilization properties for oligonucleotides containing non-telomeric residues in the 5'-region. Cross-linking studies indicate that the N-GQ domain physically contacts the 5'-region of the DNA substrate in the context of a telomerase-telomere complex. Together, these results implicate the N-GQ domain of TERT as a physical and functional constituent of the telomerase anchor site. Coupled with previous genetic analysis, our data confirm that anchor site interaction is indeed important for telomerase function in vivo.

Received for publication, March 18, 2005 , and in revised form, April 25, 2005.

This paper is dedicated to Prof. Jim Wang on the occasion of his retirement.

^* This work was supported by an R01 from the National Institutes of Health. 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 two supplemental figures and one table.

Recipient of the Irma T. Hirschl/Monique Weill-Caulier Research Award. To whom correspondence should be addressed: Dept. of Microbiology and Immunology, W. R. Hearst Microbiology Research Center, Weill Medical College of Cornell University, 1300 York Ave., NY, NY 10021. Tel.: 212-746-6506; Fax: 212-746-8587; E-mail: nflue{at}med.cornell.edu.

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