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J. Biol. Chem., Vol. 280, Issue 21, 20449-20456, May 27, 2005

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Switching Human Telomerase On and Off with hPOT1 Protein in Vitro^*

Ming Lei, Arthur J. Zaug, Elaine R. Podell, and Thomas R. Cech

From the Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215

POT1 (protection of telomeres 1) protein binds the G-rich single-stranded telomeric DNA at the ends of chromosomes. In human cells hPOT1 is involved in telomere length regulation, but the mechanism of this regulation remains unknown. Examination of the high-resolution crystal structure of the hPOT1-TTAGGGTTAG complex suggested that it would not be extended by telomerase, a hypothesis that we confirm by in vitro assays with recombinant telomerase. On the other hand, when hPOT1 is bound at a position one telomeric repeat before the 3'-end, leaving an 8-nucleotide 3'-tail, the complex is extended with improved activity and processivity. Thus, depending on its location relative to the DNA 3'-end, hPOT1 can either inhibit telomerase action or form a preferred substrate for telomerase. We propose that another factor catalyzes the interconversion of these states in vivo.

Received for publication, February 28, 2005 , and in revised form, March 23, 2005.

^* This work was supported in part by a grant 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 supplemental Fig. 1.

An Agouron/Paul Sigler research fellow of the Helen Hay Whitney Foundation. Present address: Dept. of Biological Chemistry, University of Michigan Medical School, 5413 Medical Science I, 1301 Catherine Rd., Ann Arbor, MI 48109-0606.

To whom correspondence should be addressed. Tel.: 303-492-8606; Fax: 303-492-6194; E-mail: Thomas.Cech{at}colorado.edu.

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