Isabel M. Pires
Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability
Pires, Isabel M.; Bencokova, Zuzana; Milani, Manuela; Folkes, Lisa K.; Li, Ji-Liang; Stratford, Mike R.; Harris, Adrian L.; Hammond, Ester M.
Authors
Zuzana Bencokova
Manuela Milani
Lisa K. Folkes
Ji-Liang Li
Mike R. Stratford
Adrian L. Harris
Ester M. Hammond
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
Citation
Pires, I. M., Bencokova, Z., Milani, M., Folkes, L. K., Li, J., Stratford, M. R., …Hammond, E. M. (2010). Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability. Cancer Research, 70(3), 925-935. https://doi.org/10.1158/0008-5472.CAN-09-2715
Journal Article Type | Article |
---|---|
Acceptance Date | Nov 19, 2009 |
Online Publication Date | Jan 26, 2010 |
Publication Date | Feb 1, 2010 |
Deposit Date | Nov 13, 2014 |
Publicly Available Date | Mar 28, 2024 |
Journal | Cancer Research |
Print ISSN | 0008-5472 |
Electronic ISSN | 1538-7445 |
Publisher | American Association for Cancer Research |
Peer Reviewed | Peer Reviewed |
Volume | 70 |
Issue | 3 |
Pages | 925-935 |
DOI | https://doi.org/10.1158/0008-5472.CAN-09-2715 |
Keywords | Cancer Research; Oncology |
Public URL | https://hull-repository.worktribe.com/output/466888 |
Publisher URL | http://cancerres.aacrjournals.org/content/70/3/925 |
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