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Direct Restart of a Replication Fork Stalled by a Head-On RNA Polymerase
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IFI16 senses and protects stalled replication forks
Amelia Gamble1, Thomas A Ward2, Otto P G Wheeler2
1NWCR Institute, North Wales Medical School, Brambell Building, Deiniol Rd., Bangor LL57 2UW, UK.
Molecular Cell
|January 9, 2026
Summary
Replication stress triggers inflammation without DNA damage, involving the DNA sensor IFI16. IFI16 protects stalled replication forks and is crucial for innate immunity during replication stress.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Replication stress is a major cause of DNA damage and genomic instability.
- The interplay between DNA sensing and inflammatory responses is critical for cellular homeostasis.
Purpose of the Study:
- To investigate the mechanisms by which replication stress induces inflammation.
- To elucidate the role of the DNA-sensing factor IFI16 in this process.
Main Methods:
- Utilized cell-based assays to study replication stress response.
- Investigated the interaction of IFI16 with nascent DNA at stalled replication forks.
- Analyzed signaling pathways involving STING, NF-κB, and cytokine production.
Main Results:
- Replication stress induces an inflammatory response independently of DNA damage.
- IFI16 binds nascent DNA at stalled forks and signals via STING to activate NF-κB and pro-inflammatory cytokines.
- IFI16 protects nascent DNA from nucleases and is essential for fork protection in BRCA-deficient cells.
Conclusions:
- IFI16 plays a dual role in protecting replication forks and initiating inflammatory responses during replication stress.
- IFI16 bridges innate immunity and DNA replication fork maintenance, particularly in the context of BRCA deficiency.
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