Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability.
Questions exist concerning the effects of acute versus chronic hypoxic conditions on DNA replication and genomic stability that may influence tumorigenesis. Severe hypoxia causes replication arrest independent of S-phase checkpoint, DNA damage response, or transformation status. Arrests occur during both the initiation and elongation phases of DNA replication, correlated with a rapid decrease in available deoxynucleotide triphosphates. With fluctuating oxygen tensions in tumors, arrested hypoxic cells may undergo rapid reperfusion and reoxygenation that leads to reoxygenation-induced DNA damage. In cells subjected to chronic hypoxia, we found that replicative restart was inhibited along with numerous replication factors, including MCM6 and RPA, the latter of which limits the hypoxia-induced DNA damage response. In contrast, in cells where replicative restart occurred, it was accompanied by extensive reoxygenation-induced DNA damage and compromised DNA repair. We found that cells reoxygenated after acute hypoxia underwent rapid p53-dependent apoptosis. Our findings suggest that cells lacking functional p53 are more susceptible to genomic instability and potentially tumorigenesis if they experience reoxygenation after acute exposure to hypoxia.
Pires
Isabel M
IM
The Cancer Research UK/Medical Research Council Gray Institute for Radiation Oncology and Biology, University of Oxford, Churchill Hospital, Oxford OX3 7DQ, United Kingdom.
Bencokova
Zuzana
Z
Milani
Manuela
M
Folkes
Lisa K
LK
Li
Ji-Liang
JL
Stratford
Mike R
MR
Harris
Adrian L
AL
Hammond
Ester M
EM
D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D064151:Minichromosome Maintenance Complex Component 6; D009711:Nucleotides / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D034622:RNA Interference; D051716:Replication Protein A / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D009711:Nucleotides; D051716:Replication Protein A; D016159:Tumor Suppressor Protein p53; C103258:MCM6 protein, human; D064151:Minichromosome Maintenance Complex Component 6; D010100:Oxygen