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Originally published In Press as doi:10.1074/jbc.M204111200 on June 21, 2002

J. Biol. Chem., Vol. 277, Issue 35, 31980-31987, August 30, 2002
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The Processing of Holliday Junctions by BLM and WRN Helicases Is Regulated by p53*,

Qin YangDagger , Ran ZhangDagger , Xin Wei WangDagger , Elisa A. SpillareDagger , Steven P. LinkeDagger , Deepa Subramanian§, Jack D. Griffith§, Ji Liang Li, Ian D. Hickson, Jiang Cheng Shen||, Lawrence A. Loeb||, Sharlyn J. Mazur**, Ettore Appella**, Robert M. Brosh Jr.Dagger Dagger , Parimal KarmakarDagger Dagger , Vilhelm A. BohrDagger Dagger , and Curtis C. HarrisDagger §§

From the Dagger  Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, the § Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, the  Cancer Research UK, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom, the || Gottstein Memorial Cancer Research Laboratory, Departments of Pathology and Biochemistry, University of Washington, Seattle, Washington 98195, the ** Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the Dagger Dagger  Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224

BLM, WRN, and p53 are involved in the homologous DNA recombination pathway. The DNA structure-specific helicases, BLM and WRN, unwind Holliday junctions (HJ), an activity that could suppress inappropriate homologous recombination during DNA replication. Here, we show that purified, recombinant p53 binds to BLM and WRN helicases and attenuates their ability to unwind synthetic HJ in vitro. The p53 248W mutant reduces abilities of both to bind HJ and inhibit helicase activities, whereas the p53 273H mutant loses these abilities. Moreover, full-length p53 and a C-terminal polypeptide (residues 373-383) inhibit the BLM and WRN helicase activities, but phosphorylation at Ser376 or Ser378 completely abolishes this inhibition. Following blockage of DNA replication, Ser15 phospho-p53, BLM, and RAD51 colocalize in nuclear foci at sites likely to contain DNA replication intermediates in cells. Our results are consistent with a novel mechanism for p53-mediated regulation of DNA recombinational repair that involves p53 post-translational modifications and functional protein-protein interactions with BLM and WRN DNA helicases.

* This work was supported by the Ellison Medical Foundation and National Institutes of Health Grants CA70343 and GM31819 (to J. D. G.) and by the Cancer Research UK (to I. D. H.).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.

 The on-line version of this article (available at http://www.jbc.org) contains Figs. 1-2.

§§ To whom correspondence should be addressed: LHC, NCI, National Institutes of Health, Bldg. 37, Rm. 2C05, 37 Convent Dr., Bethesda, MD 20892-4255. Tel.: 301-496-2048; Fax: 301-496-0497; E-mail: Curtis_Harris@nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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