Tumor heterogeneity includes variable and fluctuat ing oxygen concentrations, which result in the ac cumulation 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 in crease APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which under pin 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 cor related with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced repli cation catastrophe drives genomic instability in tu mors, specifically through increasing the activity of APOBEC3B.
Buffa, Francesca M.
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