Abstract
Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. 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. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.