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Estrogen receptor β-mediated nuclear interaction between IRS-1 and Rad51 inhibits homologous recombination directed DNA repair in medulloblastoma

Authors

  • Katarzyna Urbanska,

    1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania
    2. Department of Cell Biology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland
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  • Paola Pannizzo,

    1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Adam Lassak,

    1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Elisa Gualco,

    1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Eva Surmacz,

    1. Department of Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, Pennsylvania
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  • Sidney Croul,

    1. Department of Laboratory Medicine and Pathology, Toronto University, Toronto, Ontario, Canada
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  • Luis Del Valle,

    1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Kamel Khalili,

    1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Krzysztof Reiss

    Corresponding author
    1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania
    • Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Biology Life Sciences Bldg. Room 230, 1900 North 12th Street, Philadelphia, PA 19122.
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Abstract

In medulloblastomas, which are highly malignant cerebellar tumors of the childhood genotoxic treatments such as cisplatin or γ-irradiation are frequently associated with DNA damage, which often associates with unfaithful DNA repair, selection of new adaptations and possibly tumor recurrences. Therefore, better understanding of molecular mechanisms which control DNA repair fidelity upon DNA damage is a critical task. Here we demonstrate for the first time that estrogen receptor beta (ERβ) can contribute to the development of genomic instability in medulloblastomas. Specifically, ERβ was found highly expressed and active in mouse and human medulloblastoma cell lines. Nuclear ERβ was also present in human medulloblastoma clinical samples. Expression of ERβ coincided with nuclear translocation of insulin receptor substrate 1 (IRS-1), which was previously reported to interfere with the faithful component of DNA repair when translocated to the nucleus. We demonstrated that ERβ and IRS-1 bind each other, and the interaction involves C-terminal domain of IRS-1 (aa 931–1233). Following cisplatin-induced DNA damage, nuclear IRS-1 localized at the sites of damaged DNA, and interacted with Rad51—an enzymatic component of homologous recombination directed DNA repair (HRR). In medulloblastoma cells, engineered to express HRR-DNA reporter plasmid, ER antagonist, ICI 182,780, or IRS mutant (931–1233) significantly increased DNA repair fidelity. These data strongly suggest that both molecular and pharmacological interventions are capable of preventing ERβ-mediated IRS-1 nuclear translocation, which in turn improves DNA repair fidelity and possibly counteracts accumulation of malignant mutations in actively growing medulloblastomas. J. Cell. Physiol. 219: 392–401, 2009. © 2008 Wiley-Liss, Inc.

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