Skip to content

Research at St Andrews

Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signalling after nuclear DNA damage

Research output: Contribution to journalArticle


Gillian Dunphy, Sinéad M Flannery, Jessica F Almine, Dympna J Connolly, Christina Paulus, Kasper L Jonsson, Martin R Jakobsen, Michael Martin Nevels, Andrew G Bowie, Leonie Unterholzner

School/Research organisations


DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS. This non-canonical activation of STING is mediated by the DNA binding protein IFI16, together with the DNA damage response factors ATM and PARP-1, resulting in the assembly of an alternative STING signaling complex that includes the tumor suppressor p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyzes the formation of K63-linked ubiquitin chains on STING, leading to the activation of the transcription factor NF-κB and the induction of an alternative STING-dependent gene expression program. We propose that STING acts as a signaling hub that coordinates a transcriptional response depending on its mode of activation.


Original languageEnglish
Article numbere5
Pages (from-to)745-760
Number of pages22
JournalMolecular Cell
Issue number5
Publication statusPublished - 6 Sep 2018

    Research areas

  • Innate immunity, DNA damage, Etoposide, Interferon, IFI16, STING, p53, TRAF6, Ubiquitin

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Impact of human cytomegalovirus on glioblastoma cell viability and chemotherapy treatment

    dos Santos, C. J., Ferreira Castro, F. L., de Aguiar, R. B., Menezes, I. G., Santos, A. C., Paulus, C., Nevels, M. & Carlan da Silva, M. C., Sep 2018, In : Journal of General Virology. 99, 9, p. 1274-1285 12 p.

    Research output: Contribution to journalArticle

  2. Human cytomegalovirus immediate early 1 protein causes loss of SOX2 from neural progenitor cells by trapping unphosphorylated STAT3 in the nucleus

    Wu, C-C., Jiang, X., Wang, X-Z., Liu, X-J., Li, X-J., Yang, B., Ye, H-Q., Harwardt, T., Jiang, M., Xia, H-M., Wang, W., Britt, W. J., Paulus, C., Nevels, M. M. & Luo, M-H., Sep 2018, In : Journal of Virology. 92, 17, e00340-18.

    Research output: Contribution to journalArticle

  3. Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice

    Vasou, A., Paulus, C., Narloch, J., Gage, Z. O., Rameix-Welti, M-A., Eléouët, J-F., Nevels, M., Randall, R. E. & Adamson, C. S., Feb 2018, In : Antiviral Research. 150, p. 79-92

    Research output: Contribution to journalArticle

  4. ARID3B: a novel regulator of the Kaposi’s sarcoma-associated herpesvirus lytic cycle

    Wood, J., Boyne, J., Paulus, C., Jackson, B., Nevels, M. M., Whitehouse, A. & Hughes, D. J., Oct 2016, In : Journal of Virology. 90, 20, p. 9543-9555

    Research output: Contribution to journalArticle

  5. Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

    Harwardt, T., Lukas, S., Zenger, M., Reitberger, T., Danzer, D., Übner, T., Munday, D. C., Nevels, M. & Paulus, C., 7 Jul 2016, In : PLoS Pathogens. 12, 7, 39 p., e1005748.

    Research output: Contribution to journalArticle

Related by journal

  1. Structure of the CRISPR Interference complex CSM reveals key similarities with Cascade

    Rouillon, C., Zhou, M., Zhang, J., Argyris, P., Beilsten-Edmands, V., Cannone, G., Graham, S., Robinson, C., Spagnolo, L. & White, M. F., 10 Oct 2013, In : Molecular Cell. 52, 1, p. 124-134 11 p.

    Research output: Contribution to journalArticle

  2. Structure and mechanism of the CMR complex for CRISPR-Mediated antiviral immunity

    Zhang, J., Rouillon, C., Kerou, M., Reeks, J., Brugger, K., Graham, S., Reimann, J., Cannone, G., Liu, H., Albers, S-V., Naismith, J. H., Spagnolo, L. & White, M. F., 10 Feb 2012, In : Molecular Cell. 45, 3, p. 303-313 11 p.

    Research output: Contribution to journalArticle

  3. The Histone Chaperones Nap1 and Vps75 Bind Histones H3 and H4 in a Tetrameric Conformation

    Bowman, A., Ward, R., Wiechens, N., Singh, V., El Mkami, H., Norman, D. G. & Owen-Hughes, T., 18 Feb 2011, In : Molecular Cell. 41, 4, p. 398-408 11 p.

    Research output: Contribution to journalArticle

  4. ChlR1 is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance.

    Parish, J. L., Bean, AM., Park, RB. & Androphy, EJ., 28 Dec 2006, In : Molecular Cell. 24, 6, p. 867-876 10 p.

    Research output: Contribution to journalArticle

ID: 255113043