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Carcinogenesis. 2012 Nov;33(11):2026-34. doi: 10.1093/carcin/bgs239. Epub 2012 Jul 20.

Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta.

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1
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.

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.

PMID:
22822095
PMCID:
PMC3584963
DOI:
10.1093/carcin/bgs239
[Indexed for MEDLINE]
Free PMC Article

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