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Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage.
Maria Chiara Raso1, Nikola Djoric1, Franziska Walser1
1Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
The Journal of Cell Biology
|June 30, 2020
Summary
High levels of interferon-stimulated gene 15 (ISG15) accelerate DNA replication and cause DNA damage. ISG15 also sensitizes cancer cells to chemotherapy, impacting genome stability.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Biology
Background:
- The ubiquitin system regulates DNA replication, particularly under stress.
- Interferon-stimulated gene 15 (ISG15) is induced by various stressors and constitutively expressed in cancers, but its role in tumorigenesis is unclear.
Purpose of the Study:
- To investigate the role of ISG15 in DNA replication, genome stability, and cancer treatment response.
Main Methods:
- Localization studies of ISG15 at replication forks.
- Analysis of DNA synthesis, DNA damage, and chromosomal aberrations in cells with varying ISG15 levels.
- Assessment of ISG15 interaction with PCNA and RECQ1.
- Evaluation of cancer cell sensitivity to chemotherapeutic agents.
Main Results:
- ISG15 localizes with PCNA and nascent DNA at replication forks, regulating DNA synthesis.
- Elevated ISG15 accelerates replication fork progression, leading to DNA damage and chromosomal aberrations.
- ISG15's effect is independent of its conjugation and involves interaction with the DNA helicase RECQ1.
- High ISG15 levels sensitize cells to cancer chemotherapeutic treatments.
Conclusions:
- ISG15 up-regulation contributes to replication stress and impacts genome stability.
- ISG15's interaction with RECQ1 influences replication fork dynamics.
- Elevated ISG15 levels may represent a therapeutic vulnerability in cancer treatment.
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