title: Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation.
abstract: OBJECTIVE
  Non-homologous end-joining (NHEJ) and homologous recombination (HR) contribute to the repair of irradiation-induced DNA double-strand breaks (DSBs). We investigated the impact of the two major DSB repair machineries for cellular survival of human tumor cells in response to proton- and photon-irradiation.
  
  
  METHODS
  DNA damage repair and cell survival were analyzed in wildtype, HR- and NHEJ-repair-compromised and pharmacologically DNA-PKcs-inhibited human tumor cells in response to clinically relevant, low-linear energy transfer proton- and 200-keV photon-irradiation.
  
  
  RESULTS
  Pharmacological inhibition of DNA-PKcs strongly radiosensitized lung adenocarcinoma and glioblastoma cells to photon- but to a much lower extent to proton-irradiation. Enhanced radiosensitization correlated with strongly delayed repair kinetics with elevated amounts of γH2AX foci after photon-irradiation. Interestingly, we observed reduced phosphorylation of DNA-PKcs at Ser-2056 and Thr-2609 clusters after proton-irradiation compared to photon-irradiation. In contrast, A549 cells depleted of the RAD51 recombinase were markedly hypersensitive to proton-irradiation in comparison with control cells. Likewise, human BRCA2-deficient ovarian carcinoma cells were hypersensitive toward proton- in comparison with photon-irradiation.
  
  
  CONCLUSIONS
  A differential DNA damage response with enhanced susceptibility of HR-deficient tumor cells to proton-irradiation and increased sensitivity of photon-irradiated tumor cells to NHEJ inhibitors were demonstrated.
authors: Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland.
authors: Andrea O
authors: AO
authors: Fontana
authors: Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland.
authors: Marc A
authors: MA
authors: Augsburger
authors: Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland.
authors: Nicole
authors: N
authors: Grosse
authors: Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland.
authors: Matthias
authors: M
authors: Guckenberger
authors: Paul Scherrer Institute, Villigen, Switzerland.
authors: Anthony J
authors: AJ
authors: Lomax
authors: Institute of Molecular Cancer Research, University of Zurich, Switzerland.
authors: Alessandro A
authors: AA
authors: Sartori
authors: Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland. Electronic address: martin.pruschy@usz.ch.
authors: Martin N
authors: MN
authors: Pruschy
mesh_terms: D000230:Adenocarcinoma / Q000532:radiotherapy*; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D059766:DNA End-Joining Repair / Q000502:physiology / Q000528:radiation effects; D004260:DNA Repair / Q000502:physiology* / Q000528:radiation effects*; D005909:Glioblastoma / Q000532:radiotherapy*; D006801:Humans; D008175:Lung Neoplasms / Q000532:radiotherapy*; D011522:Protons; D011836:Radiation Tolerance / Q000502:physiology* / Q000528:radiation effects
chemical_list: D011522:Protons
keywords: Homologous recombination; NU7026; Non-homologous end-joining; Photon irradiation; Proton irradiation