1O - CircIGF1R_0001 mediates platinum resistance in ovarian cancer that sensitive to PARP inhibitors via promoting PARP1 binding to DNA damage sites

Background

Clinical research indicated that some platinum-resistant ovarian cancer patients are sensitive to Poly (ADP-ribose) polymerase inhibitors(PARPi) and it is associated with high Poly(ADP-ribosyl)lation (PARylation) activity of PARP1. However, the specific mechanism remains unclear.

Methods

Key functional circRNAs that promote platinum resistance in epithelial ovarian cancer（EOC）were screened and identified through next-generation sequencing, quantitative real-time polymerase chain reaction (qRT-PCR), and comet assay methods. Experiments such as RNA immunoprecipitation (RIP), RNA pull-down, laser micro-irradiation, and fluorescence colonization were used to identify the proteins and domains that interact with target circRNA. The recruitment and trapping of PARP1 at DNA damage sites were detected through Chromatin extract isolation and Biotin-tagged Nicked DNA pulled down.

Results

The circIGF1R_0001 is highly expressed in some platinum-resistant tissues and cell lines, and its overexpression enhances DNA repair and platinum resistance in ovarian cancer cells. The circIGF1R_0001 binds to the DNA binding domain of PARP1 and can be recruited together to DNA damage sites. Silencing circIGF1R_0001 significantly reduces the PARylation of PARP1, weakens the recruitment of PARP1 at DNA damage sites, and inhibits the activation of downstream DNA liag3. Furthermore, EOC patients and cell lines with platinum resistance that overexpressing circIGF1R_0001 are more sensitive to PARP inhibitors; silencing circIGF1R_0001 increases the resistance to PARPi while weakening the DNA trapping effect of PARP1.

Conclusions

1. Overexpression of circIGF1R_0001 promotes platinum resistance but also promotes sensitivity to PARPi in ovarian cancer. 2. The circIGF1R_ 0001 binds to and regulates the DBD domain of PARP1 to promote its PARylation and enhance its recruitment to DNA damage sites then enhanced the base excision repair pathway. Importantly, circIGF1R_ 0001 also enhances the DNA trapping of PARP1 by PARPi. 3. The circIGF1R_ 0001 acts as a potential biomarker for platinum resistance in ovarian cancer and a marker for screening patients who can benefit from PARPi after platinum resistance.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.