Wide-spectrum cancer killing by ENDOD1 ablation

Conventional cytotoxic cancer therapy is limited by adverse side-effects on non-affected tissues. Conversely, synthetic lethal anti-cancer approaches have the potential to reduce systemic cytotoxicity, but most potential synthetic lethality targets are not wide-spectrum and thus the subtype-specific drug targets each have limited application. We identified endonuclease D1 (ENDOD1) in a proteomic characterization of the biological response of PARP inhibition and show that ENDOD1 is recruited to PAR-positive single strand breaks, where it influences the kinetics of single-strand break repair. As with PARPi, ENDOD1 depletion triggered DNA double strand breaks in cycling cells when homologous recombination repair was defective. However, unlike PARPi, ENDOD1 depletion prompted the generation of tracts of single strand DNA in both cycling and G1 arrested p53 defective cells. This identifies a new synthetic lethal interaction that we show encompasses the majority of TP53 hotspot mutations. We conclude that ENDOD1 is a promising wide-spectrum anti-cancer drug target. ### Competing Interest Statement A patent application: Application of reagents or drugs inhibiting an endonuclease in cancer therapy (202010295776.6) was filed on April 15, 2020