Polymerase θ-what does it see, and why does it matter for cancer therapy?

Polymerase theta (Pol θ) is a DNA repair factor that has drawn much recent interest as a target for cancer therapy, since its inhibition is well-tolerated in most cells but is lethal in cancers deficient in breast cancer-associated (BRCA) genes ("synthetic lethality"). Its normal biological functions, as well as how these functions change in BRCA-deficient cancers, are only recently becoming clear, however. We review here recent progress in our understanding of the cellular regulatory mechanisms at work in determining if Pol θ sees DNA damage. At the molecular scale Pol θ then must notably see and repair diverse classes of damage, including (at least) conventional double strand breaks (made by e.g. ionizing radiation), as well as several types of damage associated with replication stress. We speculate on the mechanisms that could explain this flexibility.