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 -