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Nat Commun. 2014 Jul 31;5:4527. doi: 10.1038/ncomms5527.

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

Author information

1
Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
2
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
3
Center for Cancer Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
4
1] Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
5
Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
6
1] Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA [3] Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.
7
1] Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA [3] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.

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.

PMID:
25078033
PMCID:
PMC4130352
DOI:
10.1038/ncomms5527
[Indexed for MEDLINE]
Free PMC Article

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