IFI16 senses and protects stalled replication forks

Amelia Gamble; Thomas Ward; Otto P.G. Wheeler; Jessica Morris; Caryl Jones; Laura Bennett; Ellen Vernon; Vi Thanendran; Ilaria Ceppi; Swagata Halder; Damiano Borrello; Thomas D.J. Walker; Jahnavi Rajan; Hadeel Suleiman; Daniel Harrison; Manal Ashetiwi; Cillian Dunphy; Lucy H. Jackson-Jones; Peter Cejka; Leonie Unterholzner; Christopher Staples

doi:10.1016/j.molcel.2025.12.024

IFI16 senses and protects stalled replication forks

Amelia Gamble
, Thomas Ward
, Otto P.G. Wheeler
, Jessica Morris
, Caryl Jones
, Laura Bennett
, Ellen Vernon
, Vi Thanendran
, Ilaria Ceppi
, Swagata Halder
, Damiano Borrello
, Thomas D.J. Walker
, Jahnavi Rajan
, Hadeel Suleiman
, Daniel Harrison
, Manal Ashetiwi
, Cillian Dunphy
, Lucy H. Jackson-Jones
, Peter Cejka
, Leonie Unterholzner

Christopher Staples

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Replication stress is a key driver of DNA damage and genome instability. Here, we report that replication stress induces an inflammatory response in the absence of DNA damage. The DNA-sensing factor interferon-γ-inducible factor 16 (IFI16) binds nascent DNA at stalled replication forks and signals via the adaptor stimulator of interferon genes (STING) to induce activation of nuclear factor κB (NF-κB) and the production of pro-inflammatory cytokines, independently of the cytosolic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS). Replication stress-induced fork remodeling generates a new DNA end that is vulnerable to degradation by nucleases and is protected by a range of factors, including the tumor suppressors BRCA1 and BRCA2. IFI16 acts directly at stalled replication forks to protect nascent DNA from degradation by the nucleases MRE11, EXO1, and DNA2. Furthermore, IFI16 is required for the interferon-mediated rescue of fork protection in BRCA-deficient cells, highlighting the critical role of IFI16 in the crosstalk between innate immunity and fork protection during replication stress.

Iaith wreiddiol	Saesneg
Cyfnodolyn	Molecular Cell
Dyddiad ar-lein cynnar	8 Ion 2026
Dynodwyr Gwrthrych Digidol (DOIs)	https://doi.org/10.1016/j.molcel.2025.12.024
Statws	E-gyhoeddi cyn argraffu - 8 Ion 2026

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10.1016/j.molcel.2025.12.024Trwydded: CC BY

1-s2.0-S1097276525010238-mainFersiwn derfynol wedi’i chyhoeddi, 7.74 MBTrwydded: CC BY

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Gamble et al 2025 Final Revised Mol Cell Manuscript
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Trwydded: CC BY-NC-ND
Embargo yn dod i ben: 8/01/27

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Gamble, A., Ward, T., Wheeler, O. P. G., Morris, J., Jones, C., Bennett, L., Vernon, E., Thanendran, V., Ceppi, I., Halder, S., Borrello, D., Walker, T. D. J., Rajan, J., Suleiman, H., Harrison, D., Ashetiwi, M., Dunphy, C., Jackson-Jones, L. H., Cejka, P., ... Staples, C. (2026). IFI16 senses and protects stalled replication forks. Molecular Cell. Cyhoeddiad ar-lein ymlaen llaw. https://doi.org/10.1016/j.molcel.2025.12.024

@article{2a101997654640c1b576cd6c9c1593c7,

title = "IFI16 senses and protects stalled replication forks",

abstract = "Replication stress is a key driver of DNA damage and genome instability. Here, we report that replication stress induces an inflammatory response in the absence of DNA damage. The DNA-sensing factor interferon-γ-inducible factor 16 (IFI16) binds nascent DNA at stalled replication forks and signals via the adaptor stimulator of interferon genes (STING) to induce activation of nuclear factor κB (NF-κB) and the production of pro-inflammatory cytokines, independently of the cytosolic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS). Replication stress-induced fork remodeling generates a new DNA end that is vulnerable to degradation by nucleases and is protected by a range of factors, including the tumor suppressors BRCA1 and BRCA2. IFI16 acts directly at stalled replication forks to protect nascent DNA from degradation by the nucleases MRE11, EXO1, and DNA2. Furthermore, IFI16 is required for the interferon-mediated rescue of fork protection in BRCA-deficient cells, highlighting the critical role of IFI16 in the crosstalk between innate immunity and fork protection during replication stress.",

author = "Amelia Gamble and Thomas Ward and Wheeler, \{Otto P.G.\} and Jessica Morris and Caryl Jones and Laura Bennett and Ellen Vernon and Vi Thanendran and Ilaria Ceppi and Swagata Halder and Damiano Borrello and Walker, \{Thomas D.J.\} and Jahnavi Rajan and Hadeel Suleiman and Daniel Harrison and Manal Ashetiwi and Cillian Dunphy and Jackson-Jones, \{Lucy H.\} and Peter Cejka and Leonie Unterholzner and Christopher Staples",

year = "2026",

month = jan,

day = "8",

doi = "10.1016/j.molcel.2025.12.024",

language = "English",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

}

Gamble, A, Ward, T, Wheeler, OPG, Morris, J, Jones, C , Bennett, L, Vernon, E, Thanendran, V, Ceppi, I, Halder, S, Borrello, D, Walker, TDJ, Rajan, J, Suleiman, H , Harrison, D, Ashetiwi, M, Dunphy, C, Jackson-Jones, LH, Cejka, P, Unterholzner, L & Staples, C 2026, 'IFI16 senses and protects stalled replication forks', Molecular Cell. https://doi.org/10.1016/j.molcel.2025.12.024

TY - JOUR

T1 - IFI16 senses and protects stalled replication forks

AU - Gamble, Amelia

AU - Ward, Thomas

AU - Wheeler, Otto P.G.

AU - Morris, Jessica

AU - Jones, Caryl

AU - Bennett, Laura

AU - Vernon, Ellen

AU - Thanendran, Vi

AU - Ceppi, Ilaria

AU - Halder, Swagata

AU - Borrello, Damiano

AU - Walker, Thomas D.J.

AU - Rajan, Jahnavi

AU - Suleiman, Hadeel

AU - Harrison, Daniel

AU - Ashetiwi, Manal

AU - Dunphy, Cillian

AU - Jackson-Jones, Lucy H.

AU - Cejka, Peter

AU - Unterholzner, Leonie

AU - Staples, Christopher

PY - 2026/1/8

Y1 - 2026/1/8

N2 - Replication stress is a key driver of DNA damage and genome instability. Here, we report that replication stress induces an inflammatory response in the absence of DNA damage. The DNA-sensing factor interferon-γ-inducible factor 16 (IFI16) binds nascent DNA at stalled replication forks and signals via the adaptor stimulator of interferon genes (STING) to induce activation of nuclear factor κB (NF-κB) and the production of pro-inflammatory cytokines, independently of the cytosolic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS). Replication stress-induced fork remodeling generates a new DNA end that is vulnerable to degradation by nucleases and is protected by a range of factors, including the tumor suppressors BRCA1 and BRCA2. IFI16 acts directly at stalled replication forks to protect nascent DNA from degradation by the nucleases MRE11, EXO1, and DNA2. Furthermore, IFI16 is required for the interferon-mediated rescue of fork protection in BRCA-deficient cells, highlighting the critical role of IFI16 in the crosstalk between innate immunity and fork protection during replication stress.

AB - Replication stress is a key driver of DNA damage and genome instability. Here, we report that replication stress induces an inflammatory response in the absence of DNA damage. The DNA-sensing factor interferon-γ-inducible factor 16 (IFI16) binds nascent DNA at stalled replication forks and signals via the adaptor stimulator of interferon genes (STING) to induce activation of nuclear factor κB (NF-κB) and the production of pro-inflammatory cytokines, independently of the cytosolic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS). Replication stress-induced fork remodeling generates a new DNA end that is vulnerable to degradation by nucleases and is protected by a range of factors, including the tumor suppressors BRCA1 and BRCA2. IFI16 acts directly at stalled replication forks to protect nascent DNA from degradation by the nucleases MRE11, EXO1, and DNA2. Furthermore, IFI16 is required for the interferon-mediated rescue of fork protection in BRCA-deficient cells, highlighting the critical role of IFI16 in the crosstalk between innate immunity and fork protection during replication stress.

U2 - 10.1016/j.molcel.2025.12.024

DO - 10.1016/j.molcel.2025.12.024

M3 - Article

SN - 1097-2765

JO - Molecular Cell

JF - Molecular Cell

ER -

IFI16 senses and protects stalled replication forks

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