Hypoxia-inducible factor-1 mediates the expression of DNA polymerase iota 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 CoCl(2), enhanced the expression of DNA polymerase iota (pol iota) 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 iota gene. These results suggest that HIF-1-mediated pol iota 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.
Ito
Akiko
A
Division of Chemotherapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Koshikawa
Nobuko
N
Mochizuki
Shigenobu
S
Omura
Ken
K
Takenaga
Keizo
K
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D000094769:DNA Polymerase iota
D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D004259:DNA-Directed DNA Polymerase; D000094769:DNA Polymerase iota; C000722070:POLI protein, human