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

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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.

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

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

@article{76ba77dedcf84bebbac7fa778ad290f6,

title = "TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer",

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.",

author = "Rajat Banerjee and Nickole Russo and Min Liu and Venkatesha Basrur and Emily Bellile and Nallasivam Palanisamy and Scanlon, {Christina S.} and {Van Tubergen}, Elizabeth and Inglehart, {Ronald C.} and Tarek Metwally and Mani, {Ram Shankar} and Anastasia Yocum and Nyati, {Mukesh K.} and Castilho, {Rogerio M.} and Sooryanarayana Varambally and Chinnaiyan, {Arul M.} and D'Silva, {Nisha J.}",

note = "Funding Information: This work was supported by NIDCR DE022567, DE019513 and DE018512 (N.J.D.). This research was made possible, in part, by the use of the Cancer Center Flow-Cytometry Core that was supported by the National Institutes of Health to the University of Michigan{\textquoteright}s Cancer Center Support Grant (5P30CA46592). We are grateful to Dr V. Gorbunova, University of Rochester for providing us HR and NHEJ constructs and Dr M. Jasin (Memorial Sloan Kettering Cancer Center) for the I-SceI plasmid. We acknowledge David Adams from the University of Michigan flow cytometry core and University of Michigan Sequencing core, Microscopy and Image analysis Laboratory core and Vineeta Sharma for technical assistance.",

year = "2014",

month = jul,

day = "31",

doi = "10.1038/ncomms5527",

language = "English (US)",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer

AU - Banerjee, Rajat

AU - Russo, Nickole

AU - Liu, Min

AU - Basrur, Venkatesha

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.

N1 - Funding Information: This work was supported by NIDCR DE022567, DE019513 and DE018512 (N.J.D.). This research was made possible, in part, by the use of the Cancer Center Flow-Cytometry Core that was supported by the National Institutes of Health to the University of Michigan’s Cancer Center Support Grant (5P30CA46592). We are grateful to Dr V. Gorbunova, University of Rochester for providing us HR and NHEJ constructs and Dr M. Jasin (Memorial Sloan Kettering Cancer Center) for the I-SceI plasmid. We acknowledge David Adams from the University of Michigan flow cytometry core and University of Michigan Sequencing core, Microscopy and Image analysis Laboratory core and Vineeta Sharma for technical assistance.

PY - 2014/7/31

Y1 - 2014/7/31

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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U2 - 10.1038/ncomms5527

DO - 10.1038/ncomms5527

M3 - Article

C2 - 25078033

AN - SCOPUS:84905460114

VL - 5

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4527

ER -

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

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