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; Nisha J. D'Silva

doi:10.1038/ncomms5527

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, Nisha J. D'Silva

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

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.

Original language	English (US)
Article number	4527
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5527
State	Published - Jul 31 2014

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Banerjee, R., Russo, N., Liu, M., Basrur, V., Bellile, E., Palanisamy, N., Scanlon, C. S., Van Tubergen, E., Inglehart, R. C., Metwally, T., Mani, R. S., Yocum, A., Nyati, M. K., Castilho, R. M., Varambally, S., Chinnaiyan, A. M., & D'Silva, N. J. (2014). TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. Nature communications, 5, [4527]. https://doi.org/10.1038/ncomms5527

TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. / Banerjee, Rajat; Russo, Nickole; Liu, Min; Basrur, Venkatesha; Bellile, Emily; Palanisamy, Nallasivam; Scanlon, Christina S.; Van Tubergen, Elizabeth; Inglehart, Ronald C.; Metwally, Tarek; Mani, Ram Shankar; Yocum, Anastasia; Nyati, Mukesh K.; Castilho, Rogerio M.; Varambally, Sooryanarayana; Chinnaiyan, Arul M.; D'Silva, Nisha J.

In: Nature communications, Vol. 5, 4527, 31.07.2014.

Research output: Contribution to journal › Article › peer-review

Banerjee, R, Russo, N, Liu, M, Basrur, V, Bellile, E, Palanisamy, N, Scanlon, CS, Van Tubergen, E, Inglehart, RC, Metwally, T, Mani, RS, Yocum, A, Nyati, MK, Castilho, RM, Varambally, S, Chinnaiyan, AM & D'Silva, NJ 2014, 'TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer', Nature communications, vol. 5, 4527. https://doi.org/10.1038/ncomms5527

Banerjee, Rajat ; Russo, Nickole ; Liu, Min ; Basrur, Venkatesha ; Bellile, Emily ; Palanisamy, Nallasivam ; Scanlon, Christina S. ; Van Tubergen, Elizabeth ; Inglehart, Ronald C. ; Metwally, Tarek ; Mani, Ram Shankar ; Yocum, Anastasia ; Nyati, Mukesh K. ; Castilho, Rogerio M. ; Varambally, Sooryanarayana ; Chinnaiyan, Arul M. ; D'Silva, Nisha J. / TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. In: Nature communications. 2014 ; Vol. 5.

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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.",

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AU - Banerjee, Rajat

AU - Russo, Nickole

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AU - Bellile, Emily

AU - Palanisamy, Nallasivam

AU - Scanlon, Christina S.

AU - Van Tubergen, Elizabeth

AU - Inglehart, Ronald C.

AU - Metwally, Tarek

AU - Mani, Ram Shankar

AU - Yocum, Anastasia

AU - Nyati, Mukesh K.

AU - Castilho, Rogerio M.

AU - Varambally, Sooryanarayana

AU - Chinnaiyan, Arul M.

AU - D'Silva, Nisha J.

PY - 2014/7/31

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N2 - 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.

AB - 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.

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