Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage

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.

cGAS suppresses genomic instability as a decelerator of replication forks

“…The ability of cGAS to regulate DNA replication enables it to restrict genomic instability during S phase. A recent study showed that ISG15, a protein induced by the STING-mediated interferon response, accelerates replication fork progression and induces chromosomal breakage ( 25 ), suggesting that cGAS may affect replication forks through STING-dependent and STING-independent mechanisms in different contexts. Notably, STING is repressed in a significant fraction of cancers, rendering these cancers refractory to antitumor immunity.…”

Topoisomerase 1 dependent R-loop deficiency drives accelerated replication and genomic instability

“…Replication stress is usually characterized by fork slowing and even stalling; however other forms of replication perturbation have recently been reported, including replication fork acceleration associated with DNA damage formation [14][15][16][17][18][19][20][21][22] . Dysregulation of genes involved in mRNA biogenesis and export was reported to accelerate replication rate, potentially by impairing transcription elongation, thus reducing barriers to the replicating forks 14,15 .…”

“…Dysregulation of genes involved in mRNA biogenesis and export was reported to accelerate replication rate, potentially by impairing transcription elongation, thus reducing barriers to the replicating forks 14,15 . Overexpression of the interferon-stimulated gene 15, ISG15, was shown to accelerate replication rate via its interaction with the DNA helicase RECQ1 22 . In addition, accelerated replication rate was reported following downregulation of several origin firing factors in various organisms 17,19 .…”

“…This stress was characterized by slow replication rates, fork stalling, activation of dormant origins and even re-replication. Recently, however, several studies have found accelerated replication rates following alterations in expression of various genes [14][15][16][17][18][19][20][21][22] .…”

ISG15 fast-tracks DNA replication

“…The speed at which replication forks progress along the DNA must be tightly controlled to ensure genome stability and faithful duplication of the genome. In this issue, Raso et al (1) uncover a novel replication fork speed regulatory network controlled by the ubiquitinlike modifier interferon-stimulated gene 15 (ISG15). They propose that higher expression of ISG15 induced by interferons or commonly detected in many types of cancer cells drives deregulated fork speed, leading to DNA damage and genome instability.…”