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

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 and Lorenza Penengo ()
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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
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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41801-w

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