title: Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta.
abstract: DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt's lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control.
authors: Cancer Research UK-Medical Research Council Gray Institute for Radiation Oncology and Biology, Oncology Department, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK.
authors: Nils H
authors: NH
authors: Nicolay
authors: Rebecca
authors: R
authors: Carter
authors: Stephanie B
authors: SB
authors: Hatch
authors: Niklas
authors: N
authors: Schultz
authors: Remko
authors: R
authors: Prevo
authors: W Gillies
authors: WG
authors: McKenna
authors: Thomas
authors: T
authors: Helleday
authors: Ricky A
authors: RA
authors: Sharma
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005434:Flow Cytometry; D005720:Gamma Rays; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D016196:S Phase / Q000502:physiology* / Q000528:radiation effects; D014410:Tumor Stem Cell Assay; D000099270:Y-Family DNA Polymerases
chemical_list: D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D019384:Nucleic Acid Synthesis Inhibitors; D034741:RNA, Small Interfering; C110901:X-ray repair cross complementing protein 3; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases