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.
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Rajat
authors: R
authors: Banerjee
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Nickole
authors: N
authors: Russo
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Min
authors: M
authors: Liu
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Venkatesha
authors: V
authors: Basrur
authors: Center for Cancer Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Emily
authors: E
authors: Bellile
authors: 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.
authors: Nallasivam
authors: N
authors: Palanisamy
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Christina S
authors: CS
authors: Scanlon
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Elizabeth
authors: E
authors: van Tubergen
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Ronald C
authors: RC
authors: Inglehart
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Tarek
authors: T
authors: Metwally
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Ram-Shankar
authors: RS
authors: Mani
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Anastasia
authors: A
authors: Yocum
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Mukesh K
authors: MK
authors: Nyati
authors: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Rogerio M
authors: RM
authors: Castilho
authors: 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.
authors: Sooryanarayana
authors: S
authors: Varambally
authors: 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.
authors: Arul M
authors: AM
authors: Chinnaiyan
authors: 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.
authors: Nisha J
authors: NJ
authors: D'Silva
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007279:Injections, Subcutaneous; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; C575259:TRIP13 protein, human