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

Jia-Jia Cui1, Cheng-Xian Guo2, Jun Li3

  • 1Department of Geratic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan 410008, PR China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410008, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, Hunan 410000, PR China; Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Shenzhen Key Laboratory of Chinese Medicine Active substance screening and Translational Research, Shenzhen 518000, PR China.

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|May 21, 2025
PubMed
Abstract

Insights

Cold shock domain containing E1 (CSDE1) enhances cancer cells' resistance to genotoxic drugs by upregulating DNA repair pathways and inhibiting immune signaling. CSDE1's role as a ternary complex hub offers new strategies to improve cancer treatment sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genotoxic drug resistance is a major challenge in cancer therapy.
  • Cold shock domain containing E1 (CSDE1) has been previously linked to drug resistance.

Purpose of the Study:

  • To demonstrate CSDE1's role in regulating cellular response to genotoxic drugs.
  • To elucidate the mechanism of CSDE1 in mediating drug resistance.

Main Methods:

  • Analysis of patient samples and cancer cell lines.
  • Comet and immunofluorescence assays for DNA damage repair.
  • Systematic knockout mouse models.
  • Biotin pull-down, EMSA, and co-IP assays to study CSDE1-protein (eIF3a)-RNA (RPA2) interactions.

Main Results:

  • Elevated CSDE1 correlates with poor patient response and increased drug resistance in cell lines.
  • CSDE1 upregulates nucleotide excision repair (NER) and homologous recombination (HR) pathways.
  • CSDE1 knockout in mice increases DNA damage and inhibits the cGAS-STING pathway via RPA2.
  • CSDE1 functions as a hub for a CSDE1-eIF3a-RPA2 ternary complex.

Conclusions:

  • CSDE1 enhances resistance to genotoxic drugs through a novel mechanism.
  • The study details the zipper-like cross ternary structure of CSDE1.
  • Findings suggest CSDE1 modulation as a strategy to improve genotoxic drug sensitivity in cancer treatment.
Keywords:
CSDE1DNA repairGenotoxic drugsRPA2cGAS-STING

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