Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability.

IM Pires, Z Bencokova, M Milani, LK Folkes, JL Li, MR Stratford, AL Harris, EM Hammond

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)925–935
Number of pages11
JournalCancer Research
Volume70
Issue number3
Early online date31 Jan 2010
DOIs
Publication statusPublished - 1 Feb 2010

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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