CSDE1 enhances genotoxic drug resistance in cancer by modulating RPA2 through CSDE1-eIF3a regulatory complex

Abstract

Aims: Genotoxic drug resistance is one of the major obstacles for cancer treatment. Our previous study demonstrates that cold shock domain containing E1 (CSDE1) is associated with drug resistance. In this study, we aim to demonstrate that CSDE1 regulates cellular response to genotoxic drugs and to investigate its mechanism of action in drug resistance.

Methods: Tissues and blood samples from cancer patients were used to evaluate the relationship between CSDE1 and genotoxic drug response. Comet and immunofluorescence assays were conducted to investigate the role of CSDE1 in DNA damage repair. Systematic knockout mouse models were used to study the underlying mechanism involved. Biotin pull-down, EMSA and co-IP assays were used to probe the triplex structure of CSDE1-protein (eIF3a)-RNA (RPA2).

Results: CSDE1 elevation correlates with poor response in patient and increased resistance in cell lines to genotoxic drugs. CSDE1 upregulated the nucleotide excision repair (NER) and homologous recombination (HR) pathways. In X-ray irradiation or bleomycin-induced DNA damage mouse model, systemic CSDE1 knockout resulted in increased DNA damage. In both a CSDE1 knockout mouse model and cancer cell lines, CSDE1 inhibited the cGAS-STING pathway through RPA2. Mechanistic studies indicated that CSDE1 serves as a hub for the binding of the CSDE1-protein (eIF3a)-RNA (RPA2) ternary complex.

Conclusions: This study reveals the new role of CSDE1 in enhancing resistance to genotoxic drugs, and the detailed zipper-like cross ternary structural of CSDE1. It provides a new strategy for enhancing genotoxic drugs sensitivity.

Keywords: CSDE1; DNA repair; Genotoxic drugs; RPA2; cGAS-STING.