PARP inhibition was the first targeted therapy of synthetic lethality, based on the observation that inhibition of the BER mechanism leads to the formation and accumulation of SSBs and to the collapse of replication forks in highly replicating cancer cells, with subsequent development of DSBs that cannot be repaired through the high-fidelity HR mechanism in homozygous BRCA-defective cells, leading to apoptosis [195,196,201]. The gene discussed is PARP1; the disease is cancer.