The interferon response at the intersection of genome integrity and innate immunity.

In recent years, numerous reports indicated that, besides pathogen infections, DNA replication stress and defective DNA repair can trigger the innate immune response by introducing a state of viral mimicry, due to cytosolic accumulation of the self-nucleic acid species, which culminates in the activation of type I interferon (IFN) pathway. In turn, IFN upregulates a variety of factors mutually implicated in immune- and genome-related mechanisms, shedding light on the unprecedented causality between genome stability and innate immunity. Intriguingly, in addition to being induced by replication stress, IFN-regulated factors can also promote it, pinpointing IFN signaling as both a consequence and a cause of replication stress.

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

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 basal levels of the IFN-stimulated gene 15, ISG15, and its conjugation (ISGylation) are essential to protect nascent DNA from degradation.

Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability.

Complex mechanisms are in place to maintain genome stability. Ubiquitination of chromatin plays a central role in these mechanisms. The ever-growing complexity of the ubiquitin (Ub) code and of chromatin modifications and dynamics challenges our ability to fully understand how histone ubiquitination regulates genome stability.

Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response.

The ubiquitin system regulates the DNA damage response (DDR) by modifying histone H2A at Lys15 (H2AK15ub) and triggering downstream signaling events. Here, we find that phosphorylation of ubiquitin at Thr12 (pUbT12) controls the DDR by inhibiting the function of 53BP1, a key factor for DNA double-strand break repair by non-homologous end joining (NHEJ). Detectable as a chromatin modification on H2AK15ub, pUbT12 accumulates in nuclear foci and is increased upon DNA damage.

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

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.