Importantly, cancer cells lacking POLE3-POLE4, despite being fully competent for origin activation, present a remarkable sensitivity to ATR and PARP inhibitors; more specifically, PARPi treatment in POLE3-POLE4 KO cells unleashes replicative gap accumulation and leads to BRCA1-independent sensitization to PARPi10,11; these data are independent of Polε expression levels thus suggesting additional functions for POLE3-POLE4 in controlling DNA replication and genome stability. Here, POLE is linked to cancer.