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,...

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Veröffentlicht in:The Journal of cell biology Jg. 219; H. 8
Hauptverfasser: Raso, Maria Chiara, Djoric, Nikola, Walser, Franziska, Hess, Sandra, Schmid, Fabian Marc, Burger, Sibylle, Knobeloch, Klaus-Peter, Penengo, Lorenza
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 03.08.2020
Schlagworte:
Antineoplastic Agents - pharmacology
Bone Neoplasms - drug therapy
Bone Neoplasms - genetics
Bone Neoplasms - metabolism
Bone Neoplasms - pathology
Chromosome Breakage
Cytokines - genetics
Cytokines - metabolism
DNA Damage
DNA Replication
DNA, Neoplasm - biosynthesis
DNA, Neoplasm - genetics
Dose-Response Relationship, Drug
HEK293 Cells
HeLa Cells
Humans
MCF-7 Cells
Osteosarcoma - drug therapy
Osteosarcoma - genetics
Osteosarcoma - metabolism
Osteosarcoma - pathology
Proliferating Cell Nuclear Antigen - genetics
Proliferating Cell Nuclear Antigen - metabolism
RecQ Helicases - genetics
RecQ Helicases - metabolism
Time Factors
Ubiquitins - genetics
Ubiquitins - metabolism
ISSN:1540-8140, 1540-8140
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1540-8140
1540-8140
DOI:10.1083/jcb.202002175