Hypoxia, DNA repair gene expression and genetic instability in the tumor microenvironment

There is an emerging concept that the dysregulation of critical DNA repair pathways due to microenvironmental stresses such as hypoxia can contribute to genetic instability and tumor progression in cancer cells. In the present study, we have investigated the novel hypothesis that actual decreases in the expression of DNA repair genes may account for a proportion of hypoxia-induced genetic instability. Intriguingly, we have detected substantial alterations in the expression of several genes involved in the mismatch repair (MMR) pathway and the homologous recombination (HR) pathway of double-strand break (DSB) repair. These alterations appear to be both cell cycle- and hypoxia-inducible factor (HIF)-independent, and they persist during the post-hypoxic, reoxygenation phase. In contrast, the expression of several key proteins involved in the non-homologous end joining (NHEJ) pathway of DSB repair are not altered by hypoxia, indicating that this pathway may remain intact in hypoxic cells. Substantial decreases in HR repair were observed in hypoxic compared to normoxic cells using both extra- and intra-chromosomally-based DNA repair assays, suggesting that the observed alterations in DNA repair gene expression have functional consequences. Based on these findings, we propose a novel mechanism of genetic instability in the tumor microenvironment mediated by hypoxia-induced dysregulation of DSB repair in cancer cells. Specifically, hypoxia-mediated decreases in critical HR genes and consequently diminished HR may lead to genetic instability by shifting the balance between the high-fidelity HR and the error-prone NHEJ pathways of DSB repair. In addition, the persistence of such expression patterns during the reoxygenation phase defines a novel post-hypoxic phenotype of increased DNA damage and altered DNA repair gene expression. As both hypoxia and DNA repair gene expression independently have been shown to play critical roles in the response to chemotherapy and ionizing radiation, further elucidation of this phenomenon likely will facilitate the development of improved treatment modalities.