Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. The gene discussed is PCNA; the disease is cancer.