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Originally published In Press as doi:10.1074/jbc.M100253200 on February 8, 2001

J. Biol. Chem., Vol. 276, Issue 19, 16439-16446, May 11, 2001
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Interactions between the Werner Syndrome Helicase and DNA Polymerase delta  Specifically Facilitate Copying of Tetraplex and Hairpin Structures of the d(CGG)n Trinucleotide Repeat Sequence*

Ashwini S. Kamath-LoebDagger , Lawrence A. LoebDagger §, Erik Johansson, Peter M. J. Burgers, and Michael Fry||**

From the Dagger  Gottstein Memorial Cancer Research Laboratory, Departments of Pathology and Biochemistry, University of Washington, Seattle, Washington 98195, the  Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, and the || Unit of Biochemistry, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P. O. Box 9649, Haifa 31096, Israel

Werner syndrome (WS) is an inherited disorder characterized by premature aging and genomic instability. The protein encoded by the WS gene, WRN, possesses intrinsic 3' right-arrow 5' DNA helicase and 3' right-arrow 5' DNA exonuclease activities. WRN helicase resolves alternate DNA structures including tetraplex and triplex DNA, and Holliday junctions. Thus, one function of WRN may be to unwind secondary structures that impede cellular DNA transactions. We report here that hairpin and G'2 bimolecular tetraplex structures of the fragile X expanded sequence, d(CGG)n, effectively impede synthesis by three eukaryotic replicative DNA polymerases (pol): pol alpha , pol delta , and pol epsilon . The constraints imposed on pol delta -catalyzed synthesis are relieved, however, by WRN; WRN facilitates pol delta  to traverse these template secondary structures to synthesize full-length DNA products. The alleviatory effect of WRN is limited to pol delta ; neither pol alpha  nor pol epsilon  can traverse template d(CGG)n hairpin and tetraplex structures in the presence of WRN. Alleviation of pausing by pol delta  is observed with Escherichia coli RecQ but not with UvrD helicase, suggesting a concerted action of RecQ helicases and pol delta . Our findings suggest a possible role of WRN in rescuing pol delta -mediated replication at forks stalled by unusual DNA secondary structures.

* This work was supported by National Institutes of Health NCI Grants CA77852 and CA80993 (to L. A. L.), a grant from the Cancerfonden of the Swedish Cancer Society (to E. J.), National Institutes of Health Grant GM58534 (to P. M. J. B.), Conquer Fragile X Foundation Inc., United States-Israel Binational Science Fund, Technion Vice President for Research, and a grant from the Fund for Promotion of Research in the Technion (to M. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence may be addressed. Tel.: 206-543-6015; Fax: 206-543-3967; E-mail: laloeb@u.washington.edu.

** To whom correspondence may be addressed. Tel.: 972-4-829-5328; Fax: 972-4-851-0735; E-mail: mickey@tx.technion.ac.il.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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