Figure 6.

Repression of or mutation in several upstream regulators of homologous recombination (HR) can be synthetically lethal with PARP1 inhibition because they can cause a variety of HR repair defects that prevent fork restart. These upstream regulators include several CDKs, PTEN, USP11, and the cohesins. Inherited or acquired mutations in downstream HR components such as RAD51, MRE11, BLM, and WRN can lead to cancer. Such cancers also demonstrate synthetic lethality with PARP1 inhibition, although there could be biologically significant normal tissue toxicity when the mutation is an inherited autosomal recessive. When HR is defective in any of these cases, Pol θ inhibition would also be synthetically lethal because Pol θ is also required for the alternative nonhomologous end joining backup replication fork repair pathway.