Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells

DNA polymerase theta (Pol theta) is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS), DNA double-strand break repair and DNA replication timing. Overexpression of POLQ, the gene encoding Pol theta, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Pol theta dosage was recently suggested to promote survival of homologous recombination (HR)-deficient cancer cells, it remains unclear whether POLQ overexpression could be also beneficial to HR-proficient cancer cells. By performing a short interfering (si) RNA screen in which genes encoding druggable proteins were knocked down in Pol theta-overexpressing cells as a means to uncover genetic vulnerabilities associated with POLQ overexpression, we could not identify genes that were essential for viability in Pol theta-overexpressing cells in normal growth conditions. We also showed that, upon external DNA replication stress, Pol theta expression promotes cell survival and limits genetic instability. Finally, we report that POLQ expression correlates with the expression of a set of HR genes in breast, lung and colorectal cancers. Collectively, our data suggest that Pol theta upregulation, besides its importance for survival of HR-deficient cancer cells, may be crucial also for HR-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes.