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Title: Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance.

Authors: Chan, Norman; Koritzinsky, Marianne; Zhao, Helen; Bindra, Ranjit; Glazer, Peter M; Powell, Simon; Belmaaza, Abdellah; Wouters, Brad; Bristow, Robert G

Published In Cancer Res, (2008 Jan 15)

Abstract: Hypoxic and/or anoxic tumor cells can have increased rates of mutagenesis and altered DNA repair protein expression. Yet very little is known regarding the functional consequences of any hypoxia-induced changes in the expression of proteins involved in DNA double-strand break repair. We have developed a unique hypoxic model system using H1299 cells expressing an integrated direct repeat green fluorescent protein (DR-GFP) homologous recombination (HR) reporter system to study HR under prolonged chronic hypoxia (up to 72 h under 0.2% O(2)) without bias from altered proliferation, cell cycle checkpoint activation, or severe cell toxicity. We observed decreased expression of HR proteins due to a novel mechanism involving decreased HR protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O(2) as measured by the DR-GFP reporter system. This decrease in functional HR resulted in increased sensitivity to the DNA cross-linking agents mitomycin C and cisplatin but not to the microtubule-interfering agent, paclitaxel. Chronically hypoxic H1299 cells that had decreased functional HR were relatively radiosensitive [oxygen enhancement ratio (OER), 1.37] when compared with acutely hypoxic or anoxic cells (OER, 1.96-2.61). Using CAPAN1 cells isogenic for BRCA2 and siRNA to RAD51, we confirmed that the hypoxia-induced radiosensitivity was due to decreased HR capacity. Persistent down-regulation of HR function by the tumor microenvironment could result in low-fidelity DNA repair and have significant implications for response to therapy and genetic instability in human cancers.

PubMed ID: 18199558 Exiting the NIEHS site

MeSH Terms: Cell Hypoxia/physiology*; Cell Proliferation; Cell Survival; DNA Repair Enzymes/biosynthesis*; DNA Repair Enzymes/genetics; Drug Resistance, Neoplasm*/drug effects; Humans; Oxygen/pharmacology*; Rad51 Recombinase/biosynthesis; Rad51 Recombinase/metabolism; Radiation Tolerance*/drug effects; Recombination, Genetic*/drug effects; Recombination, Genetic*/physiology; Time Factors; Tumor Cells, Cultured

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