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

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 IFN promotes replication fork stability, cell proliferation and survival in BRCA1/2-defective cancer cells and rescues the lethality of BRCA2-deficient mouse embryonic stem cells. Although IFN activates hundreds of genes, these effects are specifically mediated by the ubiquitin-like modifier ISG15 (IFN-stimulated gene 15). Inactivation of ISG15 or of the enzymes promoting its conjugation, referred as ISGylation, completely suppresses the impact of IFN on the replication process. Depletion of ISG15 significantly reduces cell proliferation rates whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in human BRCA1-mutated triple-negative and mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, representing a novel, in-built mechanism of drug resistance linked to BRCAness.