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: Nils H Nicolay, Rebecca Carter, Stephanie B Hatch, Niklas Schultz, Remko Prevo, W Gillies McKenna, Thomas Helleday, Ricky A Sharma
• Journal: Carcinogenesis (Carcinogenesis) Vol. 33 Issue 11 Pg. 2026-34 (Nov 2012) ISSN: 1460-2180 [Electronic] England
• PMID: 22822095 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Nucleic Acid Synthesis Inhibitors
• RNA, Small Interfering
• X-ray repair cross complementing protein 3
• DNA-Directed DNA Polymerase
• Rad30 protein

Topics

• Apoptosis
• Blotting, Western
• Cell Proliferation
• Cells, Cultured
• DNA Damage (radiation effects)
• DNA Repair (radiation effects)
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• DNA-Directed DNA Polymerase (genetics, metabolism)
• Fibroblasts (cytology, metabolism, radiation effects)
• Flow Cytometry
• Gamma Rays
• Homologous Recombination (genetics)
• Humans
• Neoplasms (metabolism, pathology)
• Nucleic Acid Synthesis Inhibitors
• RNA, Small Interfering (genetics)
• Radiation Tolerance (genetics)
• S Phase (physiology, radiation effects)
• Tumor Stem Cell Assay