More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.