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

Pires, Isabel M.; Bencokova, Z; Folkes, LK; Bencokova, Zuzana; Hammond, EM; Milani, Manuela; Harris, AL; Folkes, Lisa K.; Li, JL; Li, Ji-Liang; Milani, M; Stratford, Mike R.; Pires, Isabel; Harris, Adrian L.; Stratford, MR; Hammond, Ester M.

Authors

Z Bencokova

LK Folkes

Zuzana Bencokova

EM Hammond

Manuela Milani

AL Harris

Lisa K. Folkes

JL Li

Ji-Liang Li

M Milani

Mike R. Stratford

Isabel Pires

Adrian L. Harris

MR Stratford

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

Journal Article Type Article
Publication Date Feb 1, 2010
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
Institution 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. doi:10.1158/0008-5472.CAN-09-2715
DOI https://doi.org/10.1158/0008-5472.CAN-09-2715
Keywords Cancer Research; Oncology
Publisher URL http://cancerres.aacrjournals.org/content/70/3/925