Linking DNA polymerase theta structure and function in health and disease

DNA polymerase theta (Pol theta) is an error-prone A-family polymerase that is highly conserved among multicellular eukaryotes and plays multiple roles in DNA repair and the regulation of genome integrity. Studies conducted in several model organisms have shown that Pol theta can be utilized during DNA interstrand crosslink repair and during alternative end-joining repair of double-strand breaks. Recent genetic and biochemical studies have begun to elucidate the unique structural features of Pol theta that promote alternative end-joining repair. Importantly, Pol theta-dependent end joining appears to be important for overall genome stability, as it affects chromosome translocation formation in murine and human cell lines. Pol theta has also been suggested to act as a modifier of replication timing in human cells, though the mechanism of action remains unknown. Pol theta is highly upregulated in a number of human cancer types, which could indicate that mutagenic Pol theta-dependent end joining is used during cancer cell proliferation. Here, we review the various roles of Pol theta across species and discuss how these roles may be relevant to cancer therapy.