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Originally published In Press as doi:10.1074/jbc.M101913200 on July 27, 2001

J. Biol. Chem., Vol. 276, Issue 41, 38242-38248, October 12, 2001
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Werner Syndrome Protein Is Regulated and Phosphorylated by DNA-dependent Protein Kinase*

Steven M. Yannone, Sashwati RoyDagger , Doug W. Chan, Michael B. Murphy, Shurong Huang§, Judith Campisi, and David J. Chen

From the Life Sciences Division, Department of Molecular and Cellular Biology, Lawrence Berkeley National Laboratory, Berkeley, California 94720

DNA double-strand breaks (DSBs) are a highly mutagenic and potentially lethal damage that occurs in all organisms. Mammalian cells repair DSBs by homologous recombination and non-homologous end joining, the latter requiring DNA-dependent protein kinase (DNA-PK). Werner syndrome is a disorder characterized by genomic instability, aging pathologies and defective WRN, a RecQ-like helicase with exonuclease activity. We show that WRN interacts directly with the catalytic subunit of DNA-PK (DNA-PKCS), which inhibits both the helicase and exonuclease activities of WRN. In addition we show that WRN forms a stable complex on DNA with DNA-PKCS and the DNA binding subunit Ku. This assembly reverses WRN enzymatic inhibition. Finally, we show that WRN is phosphorylated in vitro by DNA-PK and requires DNA-PK for phosphorylation in vivo, and that cells deficient in WRN are mildly sensitive to ionizing radiation. These data suggest that DNA-PK and WRN may function together in DNA metabolism and implicate WRN function in non-homologous end joining.

* This work was supported by the United States Department of Energy under Contract DE-AC03-76SF00098; by National Institutes of Health Grants AG917709 (to D. J. C.), CA50519 (to D. J. C.), AG11658 (to J. C.), and AG17242 (to J. C.); and by National Institutes of Health NIA Training Grant AG00266 (to M. B. M.).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.

Dagger Present address: Laboratory of Molecular Medicine, Ohio State University, Columbus, OH 43210-1252.

§ Present address: Palo Alto Inst. of Molecular Medicine, Mountain View, CA 94043.

To whom correspondence should be addressed: Life Sciences Div., Dept. of Molecular and Cellular Biology, Lawrence Berkeley National Laboratory, Mail Stop 74-157, 1 Cyclotron Rd., Berkeley, CA 94720. Tel.: 510-495-2861; Fax: 510-486-6816; E-mail: djchen@lbl.gov.

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


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