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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.

Original publication

DOI

10.1093/carcin/bgs239

Type

Journal article

Journal

Carcinogenesis

Publication Date

11/2012

Volume

33

Pages

2026 - 2034

Keywords

Apoptosis, Blotting, Western, Cell Proliferation, Cells, Cultured, DNA Damage, DNA Repair, DNA-Binding Proteins, DNA-Directed DNA Polymerase, Fibroblasts, Flow Cytometry, Gamma Rays, Homologous Recombination, Humans, Neoplasms, Nucleic Acid Synthesis Inhibitors, RNA, Small Interfering, Radiation Tolerance, S Phase, Tumor Stem Cell Assay