Volume 81, July 2025, 101249Author links open overlay panel, , , , , , , , , , , , , , , , , , AbstractAims

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.

AbbreviationsBCNU: Carmustine

BrdU, 5-bromo-2 '-deoxyuridine

CSDE1

cold shock domain containing E1

CCLE

Cancer Cell Line Encyclopedia

EIF3a

eukaryotic initiation factors 3a

EMSA

Electrophoretic mobility shift assay

NER

nucleotide excision repair

GDSC

Genomics of Drug Sensitivity in Cancer

HE

hematoxylin and eosinHR, homologous recombination

IRESs

internal ribosome entry sites

NHEJ

nonhomologous end joining

NSCLC

non small cell lung cancer

RPA2

replication protein A2

Keywords

CSDE1

Genotoxic drugs

DNA repair

cGAS-STING

RPA2

© 2025 The Author(s). Published by Elsevier Ltd.