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Vol. 14, Issue 10, 4221-4229, October 2003

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DNA Damage Modulates Nucleolar Interaction of the Werner Protein with the AAA ATPase p97/VCP

Juneth Joaquin Partridge ^*, Joseph Onofrio Lopreiato, Jr. , Martin Latterich , and Fred Eliezer Indig ^*  ||

^* Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; The Salk Institute, La Jolla, California 92037; and Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore Maryland 21224

Submitted February 25, 2003; Revised May 27, 2003; Accepted May 27, 2003
Monitoring Editor: Pamela Silver

We report a novel nucleolar interaction between the AAA ATPase p97/VCP and the Werner protein (WRNp), a member of the RecQ helicase family. p97/VCP mediates several important cellular functions in eucaryotic cells, including membrane fusion of the endoplasmic reticulum and Golgi and ubiquitin-dependent protein degradation. Mutations in the WRN gene cause Werner syndrome, a genetic disorder characterized by premature onset of aging symptoms, a higher incidence of cancer, and a high susceptibility to DNA damage caused by topoisomerase inhibitors. We observed that both WRNp and valosin-containing protein (VCP) were present in the nucleoplasm and in nucleolar foci in mammalian cells and that WRNp and p97/VCP physically interacted in the nucleoli. Importantly, the nucleolar WRNp/VCP complex was dissociated by treatment with camptothecin, an inhibitor of topoisomerase I, whereas other WRNp-associated protein complexes, such as WRNp/Ku 80, were not dissociated by this drug. Because WRN syndrome cells are sensitive to topoisomerase inhibitors, these observations suggest that the VCP/WRNp interaction plays an important role in WRN biology. We propose a novel role for VCP in the DNA damage response pathway through modulation of WRNp availability.

Abbreviations used: AAA, ATPases associated with diverse cellular activities; CPT, camptothecin; DAPI, 4',6-diamidino-2-phenylindole, dihydrochloride; ER, endoplasmic reticulum; GFP, green fluorescent protein; IP, immunoprecipitate; VCP, valosin-containing protein; WRNp, Werner helicase protein; WS, Werner Syndrome.

^|| Corresponding author. E-mail address: indigfr{at}grc.nia.nih.gov.

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