Juneth Joaquin Partridge, Joseph Onofrio Lopreiato, Martin Latterich, Fred Eliezer Indig
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.
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Adenosine Triphosphatases
Animals
Antigens, Nuclear
Camptothecin
Cell Cycle Proteins
Cell Nucleolus
Cells, Cultured
Cloning, Molecular
DNA Damage
DNA Helicases
DNA Topoisomerases, Type I
DNA-Binding Proteins
Endoplasmic Reticulum
Exodeoxyribonucleases
Fluorescent Antibody Technique
Golgi Apparatus
Humans
K562 Cells
Ku Autoantigen
Membrane Fusion
Mice
Mutation
Protein Binding
Protein Structure, Tertiary
RecQ Helicases
Valosin Containing Protein
Werner Syndrome
Werner Syndrome Helicase
