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

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.

New insights into the interaction between m6A modification and lncRNA in cancer drug resistance

“…The microprotein DDUP, which is encoded by lncRNA CTBP1‐DT, exhibited a significant increase in cisplatin‐resistant ovarian cancer cells. Furthermore, there was an inverse correlation between the expression of DDUP and the response to cisplatin‐based therapy 81 . Similarly, lncRNA SCAT7 is upregulated in response to DNA‐damaging drugs such as cisplatin.…”

“…Furthermore, there was an inverse correlation between the expression of DDUP and the response to cisplatin‐based therapy. 81 Similarly, lncRNA SCAT7 is upregulated in response to DNA‐damaging drugs such as cisplatin. In addition, it has been established that lncRNA MALAT1 functions as a competing endogenous RNA, absorbing miR‐146a and miR‐216b.…”

The roles of long non-coding RNAs in ovarian cancer: from functions to therapeutic implications

“…(IV) LncRNA acting as microRNAs (miRNAs) sponges to regulate the expression of their targets ( 45 , 46 ). (V) Interestingly, a few lncRNAs bind to ribosomes and translate peptide products ( 47 ).…”

Small but mighty: the rise of microprotein biology in neuroscience

“…As neurons are post-mitotic, they rely on non-homologous end joining (NHEJ) rather than homologous repair, which requires mitotic DNA replication. While microproteins involved in nuclear function have not been characterized in neurons to date, the DDUP microprotein encoded by the DNA damage-induced lncRNA CTBP1-DT protects cells from DNA damage, likely through binding to the DNA repair factor RAD18 (Ren et al, 2023 ). Furthermore, the microprotein CYREN (also known as MRI-2) binds to Ku to regulate NHEJ and double-stranded break repair (Slavoff et al, 2014 ; Arnoult et al, 2017 ).…”