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Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15

Author

Listed:
  • Ramona N. Moro

    (University of Zurich, Institute of Molecular Cancer Research)

  • Uddipta Biswas

    (University of Zurich, Institute of Molecular Cancer Research)

  • Suhas S. Kharat

    (National Cancer Institute, National Institutes of Health)

  • Filip D. Duzanic

    (University of Zurich, Institute of Molecular Cancer Research)

  • Prosun Das

    (Erasmus MC Cancer Institute, Erasmus University Medical Center)

  • Maria Stavrou

    (University of Zurich, Institute of Molecular Cancer Research)

  • Maria C. Raso

    (University of Zurich, Institute of Molecular Cancer Research)

  • Raimundo Freire

    (Unidad de Investigación, Hospital Universitario de Canarias
    Universidad de La Laguna
    Universidad Fernando Pessoa Canarias)

  • Arnab Ray Chaudhuri

    (Erasmus MC Cancer Institute, Erasmus University Medical Center)

  • Shyam K. Sharan

    (National Cancer Institute, National Institutes of Health)

  • Lorenza Penengo

    (University of Zurich, Institute of Molecular Cancer Research)

Abstract

DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that basal levels of the IFN-stimulated gene 15, ISG15, and its conjugation (ISGylation) are essential to protect nascent DNA from degradation. Moreover, IFNβ treatment restores replication fork stability in BRCA1/2-deficient cells, which strictly depends on topoisomerase-1, and rescues lethality of BRCA2-deficient mouse embryonic stem cells. Although IFNβ activates hundreds of genes, these effects are specifically mediated by ISG15 and ISGylation, as their inactivation suppresses the impact of IFNβ on DNA replication. ISG15 depletion significantly reduces cell proliferation rates in human BRCA1-mutated triple-negative, whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, which we propose as an in-built mechanism of drug resistance linked to BRCAness.

Suggested Citation

  • Ramona N. Moro & Uddipta Biswas & Suhas S. Kharat & Filip D. Duzanic & Prosun Das & Maria Stavrou & Maria C. Raso & Raimundo Freire & Arnab Ray Chaudhuri & Shyam K. Sharan & Lorenza Penengo, 2023. "Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41801-w
    DOI: 10.1038/s41467-023-41801-w
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