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

Rajat Banerjee, Nickole Russo, Min Liu, Venkatesha Basrur, Emily Bellile, Nallasivam Palanisamy, Christina S. Scanlon, Elizabeth van Tubergen, Ronald C. Inglehart, Tarek Metwally, Ram-Shankar Mani, Anastasia Yocum, Mukesh K. Nyati, Rogerio M. Castilho, Sooryanarayana Varambally, Arul M. Chinnaiyan and Nisha J. D’Silva ()
Additional contact information
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
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
Arul M. Chinnaiyan: University of Michigan
Nisha J. D’Silva: School of Dentistry, University of Michigan

Nature Communications, 2014, vol. 5, issue 1, 1-18

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5527

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