T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51

Authors

  • Joanna Trojanek,

    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
    2. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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  • Sidney Croul,

    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
    2. Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
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  • Thu Ho,

    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
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  • Jin Ying Wang,

    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
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  • Armine Darbinyan,

    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
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  • Michal Nowicki,

    1. Center for Biotechnology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
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  • Luis Del Valle,

    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
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  • Tomasz Skorski,

    1. Center for Biotechnology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
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  • Kamel Khalili,

    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
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  • Krzysztof Reiss

    Corresponding author
    1. Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania
    • Center for Neurovirology and Cancer Biology, Temple University, 1900 North 12th Street, Biology Life Science Building, Philadelphia, PA 19122.

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Abstract

JC polyomavirus (JCV), which infects 90% of the human population, is detectable in human tumors. Its early protein, JCV T-antigen, transforms cells in vitro and is tumorigenic in experimental animals. Although T-antigen-mediated transformation involves genetic alterations of the affected cells, the mechanism underlying this genomic instability is not known. We show that JCV T-antigen inhibits homologous recombination DNA repair (HRR), which results in an accumulation of mutations. T-antigen does not operate directly but utilizes a cytosolic molecule, insulin receptor substrate 1 (IRS-1). Following T-antigen-mediated nuclear translocation, IRS-1 binds Rad51 at the site of damaged DNA. This T-antigen-mediated inhibition of HRR does not function in cells lacking IRS-1, and can be reproduced in the absence of T-antigen by IRS-1 with artificial nuclear localization signal. Our observations define a new mechanism by which viral protein utilizes cytosolic molecule to inhibit faithful DNA repair, and suggest how polyomaviruses could compromise stability of the genome. © 2005 Wiley-Liss, Inc.

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