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J. Biol. Chem., Vol. 283, Issue 11, 6935-6941, March 14, 2008

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Tethering Telomeric Double- and Single-stranded DNA-binding Proteins Inhibits Telomere Elongation^*

Katherine T. Etheridge, Sarah A. Compton, Katharine S. Barrientos, Sezgin Ozgur, Jack D. Griffith, and Christopher M. Counter¹

From the Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710 and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Mammalian telomeres are composed of G-rich repetitive double-stranded (ds) DNA with a 3' single-stranded (ss) overhang and associated proteins that together maintain chromosome end stability. Complete replication of telomeric DNA requires de novo elongation of the ssDNA by the enzyme telomerase, with telomeric proteins playing a key role in regulating telomerase-mediated telomere replication. In regards to the protein component of mammalian telomeres, TRF1 and TRF2 bind to the dsDNA of telomeres, whereas POT1 binds to the ssDNA portion. These three proteins are linked through either direct interactions or by the proteins TIN2 and TPP1. To determine the biological consequence of connecting telomeric dsDNA to ssDNA through a multiprotein assembly, we compared the effect of expressing TRF1 and POT1 in trans versus in cis in the form of a fusion of these two proteins, on telomere length in telomerase-positive cells. When expressed in trans these two proteins induced extensive telomere elongation. Fusing TRF1 to POT1 abrogated this effect, inducing mild telomere shortening, and generated looped DNA structures, as assessed by electron microscopy, consistent with the protein forming a complex with dsDNA and ssDNA. We speculate that such a protein bridge between dsDNA and ssDNA may inhibit telomerase access, promoting telomere shortening.

Received for publication, October 22, 2007 , and in revised form, January 2, 2008.

^* This work was supported by National Institutes of Health Grants CA82481, GM31819, and ES13773, the Werner and Elaine Dannheisser Fund for Research in the Biology of Aging of the Lymphoma Foundation (to C. M. C.), and the Department of Defense Breast Cancer Research Program (to K. T. E.). 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.

¹ To whom correspondence should be addressed: DUMC-3813, Durham, NC 27710. Tel.: 919-684-9890; Fax: 919-684-8958; E-mail: count004{at}mc.duke.edu.

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