Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation of a number of DNA damage response and repair genes. This can lead to inhibition of recombination-mediated repair of DNA double-strand breaks. Hypoxia can also increase the rate of mutation. Therefore, tumor cell adaptation to the hypoxic microenvironment can drive genetic instability and malignant progression. In this review, we focus on hypoxia-mediated genetic instability in the context of aberrant DNA damage signaling and DNA repair. Additionally, we discuss potential therapeutic approaches to specifically target repair-deficient hypoxic tumor cells.
SummaryHypoxic cells have been linked to genetic instability and tumor progression. However, little is known about the exact relationship between DNA repair and genetic instability in hypoxic cells. We therefore tested whether the sensing and repair of DNA double-strand breaks (DNA-dsbs) is altered in irradiated cells kept under continual oxic, hypoxic or anoxic conditions. Synchronized G0-G1 human fibroblasts were irradiated (0-10 Gy) after initial gassing with 0% O 2 (anoxia), 0.2% O 2 (hypoxia) or 21% O 2 (oxia) for 16 hours. The response of phosphorylated histone H2AX (c-H2AX), phosphorylated ataxia telangiectasia mutated [ATM(Ser1981)], and the p53 binding protein 1 (53BP1) was quantified by intranuclear DNA repair foci and western blotting. At 24 hours following DNA damage, residual c-H2AX, ATM(Ser1981) and 53BP1 foci were observed in hypoxic cells. This increase in residual DNA-dsbs under hypoxic conditions was confirmed using neutral comet assays. Clonogenic survival was also reduced in chronically hypoxic cells, which is consistent with the observation of elevated G1-associated residual DNA-dsbs. We also observed an increase in the frequency of chromosomal aberrations in chronically hypoxic cells. We conclude that DNA repair under continued hypoxia leads to decreased repair of G1-associated DNA-dsbs, resulting in increased chromosomal instability. Our findings suggest that aberrant DNA-dsb repair under hypoxia is a potential factor in hypoxia-mediated genetic instability.Key words: DNA double-strand breaks, hypoxia, non-homologous end joining, DNA double-strand break sensors, c-H2AX, genetic instability Introduction Human cells have evolved specific pathways to repair DNA double-strand breaks (DNA-dsbs) and enact cell cycle checkpoints following DNA damage to ensure genetic stability. These pathways could be oxygen sensitive because endogenous and exogenous DNA damage can be differentially processed and repaired in oxic versus hypoxic cells Bristow and Hill, 2008). For example, intratumoral hypoxia can drive genetic instability and accelerate tumor progression. It can also lead to altered radio-or chemoresistance, enhanced mutagenesis, impaired DNA repair and increased systemic metastasis (reviewed by Bindra et al., 2007;Bristow and Hill, 2008;Huang et al., 2007). The consequence of hypoxic exposure on DNA damage response (DDR) sensing and signalling might relate, in part, to the oxygen level (e.g. hypoxia or anoxia) and the duration of the hypoxic exposure (acute or cycling hypoxia versus chronic or prolonged hypoxia).One of the most lethal DNA lesions is a DNA-dsb. Incorrectly or non-repaired DNA-dsbs could result in chromosomal deletions, amplifications, aneuploidy and genetic instability (Helleday et al., 2007). Despite the fact that the vast majority of human tumors contain hypoxic sub-regions, little is known about the potential effects of continual hypoxia on DNA-dsb sensing and processing. The signal transduction processes in response to DNA-dsbs are dependent on the kinase activity and autophos...
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