Effects of Acute versus Chronic Hypoxia on DNA Damage Responses and Genomic Instability

TLDR

Acute and chronic hypoxia differentially affect DNA replication and genomic stability, with severe hypoxia causing replication arrest during initiation and elongation independent of checkpoint activation and linked to dNTP depletion. In tumors with fluctuating oxygen levels, reoxygenation of hypoxia‑arrested cells induces DNA damage. Chronic hypoxia impairs replicative restart and depletes replication factors such as MCM6 and RPA, whereas reoxygenation after acute hypoxia triggers p53‑dependent apoptosis but, in p53‑deficient cells, causes extensive DNA damage, compromised repair, and increased genomic instability that may drive tumorigenesis.

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.