Hypoxia-inducible factor-1 mediates the expression of DNA polymerase ι in human tumor cells

Hypoxia generated in tumors has been shown to contribute to mutations and genetic instability. However, the molecular mechanisms remain incompletely defined. Since reactive oxygen species (ROS) are overproduced immediately after reoxygenation of hypoxic cells and generate oxidized guanine, we assumed that the mechanisms might involve translesion DNA polymerases that can bypass oxidized guanine. We report here that hypoxia as well as hypoxia mimetics, desferrioxamine, and CoCl2, enhanced the expression of DNA polymerase ι (pol ι) in human tumor cell lines. Searching the consensus sequence of hypoxia response element to which HIF-1 binds revealed that it locates in the intron 1 of the pol ι gene. These results suggest that HIF-1-mediated pol ι gene expression may be involved in the generation of translesion mutations during DNA replication after hypoxia followed by reoxygenation, thereby contributing to the accumulation of genetic changes in tumor cells.