DNA损伤应答（DDR）信号的持续激活已被证明在癌症化疗失败中发挥重要作用。然而，癌细胞中DDR持续的机制仍不清楚。在本研究中，我们发现编码为CTBP1-DT长链非编码RNA的DDUP微蛋白的表达在顺铂耐药性卵巢癌细胞中大幅增加，并且与顺铂为基础的治疗反应呈负相关。使用患者衍生的人类癌细胞模型，我们观察到DNA损伤引起的DDUP聚焦使RAD18/RAD51C和RAD18/PCNA复合物在DNA损伤位点上持续存在，从而通过双重RAD51C介导的同源重组（HR）和增殖细胞核抗原（PCNA）介导的后复制修复（PRR）机制导致顺铂抗药性。值得注意的是，ATR抑制剂的治疗破坏了DDUP/RAD18的相互作用，并消除了DDUP对延长DNA损伤信号的影响，从而导致卵巢癌细胞在体内对顺铂为基础的治疗产生高敏感性。总的来说，我们的研究揭示了DDUP介导的异常DDR信号与顺铂抗药性的关系，并描述了一种潜在的治疗方案，用于管理铂类耐药性卵巢癌。© 2023年。作者(s)。

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.© 2023. The Author(s).