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J. Biol. Chem., Vol. 280, Issue 37, 32069-32080, September 16, 2005

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POT1 Stimulates RecQ Helicases WRN and BLM to Unwind Telomeric DNA Substrates^*

Patricia L. Opresko1, Penelope A. Mason, Elaine R. Podell¶, Ming Lei¶2, Ian D. Hickson**, Thomas R. Cech¶, and Vilhelm A. Bohr3

From the Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, Maryland 21224, ^¶Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, and ^**Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom

Defects in human RecQ helicases WRN and BLM are responsible for the cancer-prone disorders Werner syndrome and Bloom syndrome. Cellular phenotypes of Werner syndrome and Bloom syndrome, including genomic instability and premature senescence, are consistent with telomere dysfunction. RecQ helicases are proposed to function in dissociating alternative DNA structures during recombination and/or replication at telomeric ends. Here we report that the telomeric single-strand DNA-binding protein, POT1, strongly stimulates WRN and BLM to unwind long telomeric forked duplexes and D-loop structures that are otherwise poor substrates for these helicases. This stimulation is dependent on the presence of telomeric sequence in the duplex regions of the substrates. In contrast, POT1 failed to stimulate a bacterial 3 '–5'-helicase. We find that purified POT1 binds to WRN and BLM in vitro and that full-length POT1 (splice variant 1) precipitates a higher amount of endogenous WRN protein, compared with BLM, from the HeLa nuclear extract. We propose roles for the cooperation of POT1 with RecQ helicases WRN and BLM in resolving DNA structures at telomeric ends, in a manner that protects the telomeric 3 ' tail as it is exposed during unwinding.

Received for publication, May 11, 2005 , and in revised form, July 18, 2005.

^* 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 Figs. 1–3.

¹ Present address: Dept. of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, 100 Technology Dr., Pittsburgh, PA 15260.

² Present address: Dept. of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0606.

³ To whom correspondence should be addressed: Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224. Tel.: 410-558-8162; E-mail: vbohr{at}nih.gov.

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