Loss of CHTF18–RFC2/5 leads to replicative gaps and sensitivity to PARP inhibitors

Abstract The use of PARP inhibitors (PARPi) has profoundly changed the treatment of BRCA1/BRCA2-mutated cancers. Despite this, acquired resistance to PARPi has become a major challenge in the clinic. Hence, a more detailed understanding of the mechanisms underlying PARPi sensitivity is crucially needed. Here, we show that loss of the alternative clamp loader complex CHTF18–RFC2/5 leads to a remarkable sensitization to PARPi. Loss of CHTF18 is not associated with defective RAD51 foci formation excluding a defect in homologous recombination. On the contrary, treatment with PARPi triggers replicative gap accumulation in CHTF18 knockout (KO) cells. By performing transient silencing experiments, we highlight PARP1–PARP2 trapping at replicative gaps as a major determinant of sensitivity to these compounds. Crucially, loss of 53BP1 does not rescue PARPi sensitivity in CHTF18 KO cells, outlining Polε and the CHTF18–RFC2/5 complex as potential novel targets for cancer therapeutics.