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TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer

Author

Listed:
  • Rajat Banerjee

    (School of Dentistry, University of Michigan)

  • Nickole Russo

    (School of Dentistry, University of Michigan)

  • Min Liu

    (School of Dentistry, University of Michigan)

  • Venkatesha Basrur

    (University of Michigan)

  • Emily Bellile

    (Center for Cancer Biostatistics, University of Michigan)

  • Nallasivam Palanisamy

    (University of Michigan
    Michigan Center for Translational Pathology, University of Michigan)

  • Christina S. Scanlon

    (School of Dentistry, University of Michigan)

  • Elizabeth van Tubergen

    (School of Dentistry, University of Michigan)

  • Ronald C. Inglehart

    (School of Dentistry, University of Michigan)

  • Tarek Metwally

    (School of Dentistry, University of Michigan)

  • Ram-Shankar Mani

    (University of Michigan)

  • Anastasia Yocum

    (University of Michigan)

  • Mukesh K. Nyati

    (University of Michigan)

  • Rogerio M. Castilho

    (School of Dentistry, University of Michigan)

  • Sooryanarayana Varambally

    (University of Michigan
    Michigan Center for Translational Pathology, University of Michigan)

  • Arul M. Chinnaiyan

    (University of Michigan
    Michigan Center for Translational Pathology, University of Michigan
    University of Michigan)

  • Nisha J. D’Silva

    (School of Dentistry, University of Michigan
    University of Michigan
    Michigan Center for Translational Pathology, University of Michigan)

Abstract

Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.

Suggested Citation

  • Rajat Banerjee & Nickole Russo & Min Liu & Venkatesha Basrur & Emily Bellile & Nallasivam Palanisamy & Christina S. Scanlon & Elizabeth van Tubergen & Ronald C. Inglehart & Tarek Metwally & Ram-Shanka, 2014. "TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer," Nature Communications, Nature, vol. 5(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5527
    DOI: 10.1038/ncomms5527
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