title: DNA damage modulates nucleolar interaction of the Werner protein with the AAA ATPase p97/VCP.
abstract: 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.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Juneth Joaquin
authors.initials: JJ
authors.lastname: Partridge
authors.forename: Joseph Onofrio
authors.initials: JO
authors.lastname: Lopreiato
authors.forename: Martin
authors.initials: M
authors.lastname: Latterich
authors.forename: Fred Eliezer
authors.initials: FE
authors.lastname: Indig
mesh_terms: D000251:Adenosine Triphosphatases; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002466:Cell Nucleolus / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004249:DNA Damage / Q000502:physiology*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005090:Exodeoxyribonucleases; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D000072200:Ku Autoantigen; D008561:Membrane Fusion / Q000502:physiology; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053484:RecQ Helicases; D000074405:Valosin Containing Protein; D014898:Werner Syndrome / Q000235:genetics / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005090:Exodeoxyribonucleases; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; D000072200:Ku Autoantigen; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin