Abstract
Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B.
Highlights
Hypoxia, which is defined as conditions of insufficient oxygen, is associated with the resistance of tumors to standard therapies and poor patient prognosis [1,2]
Our studies have shown that radiobiological hypoxia induced replication stress, which includes the rapid accumulation of single stranded DNA, leads to a DNA damage response (DDR) [8]
We have demonstrated that the biological response to replication stress is determined by the level of accompanying DNA damage
Summary
Hypoxia, which is defined as conditions of insufficient oxygen, is associated with the resistance of tumors to standard therapies and poor patient prognosis [1,2]. Radiobiological hypoxia is unusual in that the induction of replication stress does not lead to an apparent accumulation of DNA damage, which suggests that the level of replication stress is transient or mitigated by other factors [9,10]. This lack of associated DNA damage observed in hypoxia, even after prolonged exposures, might indicate that despite a robust replication stress response, damage is avoided potentially by reduced DNA replication/transcription rates [10,11]. A number of commonly used pharmacological agents, which lead to replication fork stalling, have been shown to lead to DNA damage and this has been attributed to RPA exhaustion resulting in replication catastrophe [12]
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