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The ubiquitin-like modifier ISG15 (Interferon-Stimulated Gene 15) is strongly induced by interferons, bacterial and viral infection. ISG15 and its conjugation – a process called ISGylation – are also induced by different genotoxic treatments and UV light. Moreover, ISG15 can act as free intracellular or secreted molecule, making the ISG15 system rather complex. Recently reported to be deregulated in most human malignancies, ISG15 is emerging as an important oncoprotein and a potential diagnostic and therapeutic target for cancer. Even though many proteomic studies identified different proteins involved in DNA repair and DNA replication as potential targets of ISG15, a functional and comprehensive analysis of these factors is still missing.
Deciphering the role of ISG15 – both as free molecule or conjugated to targets – in the maintenance of genome integrity, by focusing on their specific role in the DNA damage response and DNA replication.
By combining different experimental approaches, we found that cells expressing high levels of ISG15, as upon interferon stimulation and in many cancer cells, show an increased and deregulated DNA replication fork progression associated with genomic lesions and chromosomal aberrations.
This phenotype, which is further exacerbated by mild doses of genotoxic stress, is largely conjugation-independent and relies on the activity of the helicase RECQ1, which promotes the restart of stalled forks. All these data have important clinical implications, suggesting that infections by pathogens or conditions of chronic inflammation may expose to genotoxic stress during replication.
We are currently characterizing the diverse effects that the interferon system, and ISG15 itself, have on the regulation of unperturbed DNA replication and upon replication stress, by adopting different genetic contexts and conditions.
Raso MC, Djoric N, Walser F, Hess S, Schmid FM, Burger S, Knobeloch KP, Penengo L. Interferon-Stimulated Gene 15 accelerates replication fork progression inducing chromosomal breakage. Journal of Cell Biology (2020).
