The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers chemoresistance in ovarian cancer

Abstract

Abstract Aberrant DNA damage response (DDR) signaling is one of major reasons underlying chemotherapy failure in cancer, and understanding the mechanism underlying aberrant DDR signaling would aid in developing novel strategies for overcoming cancer chemoresistance. The present study demonstrated that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, increased in chemotherapy non-response ovarian cancer cells and was inversely correlated to platinum-based chemotherapy response. Using a patient-derived human cancer cell model, we observed that the formation of DDUP foci, which is induced by DNA damage, played an important role in platinum-based chemotherapy resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. These mechanisms are mediated via interactions with RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage and sustained RAD18-mediated DNA damage signaling. 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 platinum-based chemotherapy in vivo. Altogether, the study provides insights into DDUP-mediated aberrant DDR signaling in cancer chemoresistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.