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MBC in Press, published online ahead of print August 22, 2003
Mol. Biol. Cell 10.1091/mbc.E03-02-0111

A more recent version of this article appeared on October 1, 2003
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Submitted on February 25, 2003
Revised on May 27, 2003
Accepted on May 27, 2003

DNA damage modulates Nucleolar interaction of the Werner protein with the AAA ATPase p97/VCP

Juneth Joaquin Partridge1, Joseph Lopreiato2, Martin Latterich3, and Fred Eliezer Indig4*

1 Laboratory of Cell Biology, CCR, NCI, National Institutes of Health, Bethesda, MD 20892
2 Laboratory of Molecular Pharmacology, CCR, NCI, National Institutes of Health, Bethesda, MD 20892
3 The Salk Institute, La Jolla, CA 92037
4 Laboratory of Cell Biology, CCR, NCI, National Institutes of Health, Bethesda, MD 20892 and Laboratory of Molecular Gerontology, NIA, NIH, Baltimore MD 21224

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

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 ER and Golgi and ubiquitin dependant 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 WRN and 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. As WRN syndrome cells are sensitive to topoisomerase inhibitors, these observations suggest that the VCP/WRN 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.






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