Abstract
DNA replication is highly regulated by the ubiquitin system, which plays key roles upon stress. The ubiquitin-like modifier ISG15 (interferon-stimulated gene 15) is induced by interferons, bacterial and viral infection, and DNA damage, but it is also constitutively expressed in many types of cancer, although its role in tumorigenesis is still largely elusive. Here, we show that ISG15 localizes at the replication forks, in complex with PCNA and the nascent DNA, where it regulates DNA synthesis. Indeed, high levels of ISG15, intrinsic or induced by interferon-β, accelerate DNA replication fork progression, resulting in extensive DNA damage and chromosomal aberrations. This effect is largely independent of ISG15 conjugation and relies on ISG15 functional interaction with the DNA helicase RECQ1, which promotes restart of stalled replication forks. Additionally, elevated ISG15 levels sensitize cells to cancer chemotherapeutic treatments. We propose that ISG15 up-regulation exposes cells to replication stress, impacting genome stability and response to genotoxic drugs.
Highlights
And accurate DNA replication in dividing cells is crucial to maintain the integrity of the human genome
ISG15 is localized at the DNA replication forks To gain insight into the potential effect of ISG15 in the regulation of genome stability, we developed different systems to modulate ISG15 expression
To validate the presence of ISG15 in chromatin compartments, we employed the isolation of proteins on nascent DNA technique, which allows the isolation of proteins bound, directly or indirectly, to nascent DNA at the replication forks (Sirbu et al, 2011)
Summary
And accurate DNA replication in dividing cells is crucial to maintain the integrity of the human genome. The mechanisms that underlie the cellular DNA damage response and DNA replication stress are complex and tightly controlled by posttranslational protein modifications, including phosphorylation, acetylation, methylation, poly-(ADP-ribosyl)ation, and modifications by the ubiquitin system (Wang et al, 2017). Ubiquitin and UBLs have pivotal roles in the cellular response to various forms of stress and mainly act via covalent conjugation to target proteins. This kind of protein modification can affect stability, subcellular localization, activity, and overall function (Wang et al, 2017). The function of most UBLs, including ISG15 (the first UBL identified), in genome stability is largely unknown
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