My laboratory studies DNA double strand breaks (DSBs)1. Two primary pathways are utilized to repair DSBs2, Homology directed repair (HDR) and classical non-homologous end joining (c-NHEJ)3. An alternative NHEJ pathway (a-NHEJ) functions when c-NHEJ has been disabled4, and DNA polymerase theta (polQ) is central to this pathway5. This was first shown by studying DSBs at G-quadruplexes6. DNA repair factors function as tumor suppressors7, and defects in HDR or c-NHEJ promote genomic instability and cancer8. Although polQ deficiency promotes genomic instability, lack of polQ does not promote cancer. In fact, loss of polQ protects ATM deficient mice from thymic lymphoma9. Moreover, polQ is over-expressed in numerous cancers [breast, stomach, lung, colon, lymphoid, skin] and overexpression is highly correlated with poorer outcomes10-12. Thus, polQ actually shares some characteristics with tumor oncogenes. It has been shown that the G-quadruplex binding drug, pyridostatin, induces DSBs13. We examined numerous c-NHEJ defective cells and establish that all the core c-NHEJ components are essential for maximal cell survival after pyridostatin exposure. In contrast (and to our surprise), polQ ablation markedly enhances cell survival after pyridostatin exposure. We suggest a model whereby pyridostatin and polQ become trapped at G-quadruplex structures during replication causing replication fork collapse and DSBs. More importantly, these preliminary data suggest that the many cancer types that overexpress polQ might be particularly sensitive to drugs that target G-quadruplex structures and suggest an obvious synthetic lethal approach to enhance therapeutics that target G-quadruplexes.
A significant research effort has been put forth towards personalized cancer therapies that rely on the ability to predict what cancers are sensitive to which therapies; another significant research effort has focused on targeting specific DNA structures, G-quadruplexes that are highly represented in genes that promote tumorigenesis. We have discovered that drugs that target G-quadruplexes are most effective in cells that express a particular DNA polymerase, DNA pol theta. The focus of the proposed research is to define how overexpression of DNA pol theta sensitizes cancer cells to drugs that target G-quadruplexes and whether this observation can be exploited to develop better strategies to treat the many cancer types that overexpress DNA pol theta.
