DNA is strictly compartmentalized within the nucleus to prevent autoimmunity1; despite this, cyclic GMP–AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage2,3,4,5,6. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis7, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.

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We thank J. Rehwinkel, N. Hastie, I. Adams, D. Papadopoulos, C. Ponting and W. Bickmore for discussions and comments on the manuscript; A. Wood, G. Taylor, D. Jamieson, H. Kato, P. Gao and B. Ramsahoye for technical advice and assistance; K. S. Mackenzie, P. Vagnarelli, H. Kato and T. Fujita for sharing reagents; R. Greenberg for discussion of unpublished data; the IGMM Transgenic, Sequencing, Imaging and Flow Cytometry facilities; and C. Nicol and A. Colley for graphics assistance. This work was funded by the Medical Research Council HGU core grant (MRC, U127580972) (A.P.J., N.G.), Newlife the Charity for Disabled Children (K.J.M.), the Wellcome Trust–University of Edinburgh Institutional Strategic Support Fund 2 (K.J.M.), MRC Discovery Award (MC_PC_15075, T.C.), an International Early Career Scientist grant from the Howard Hughes Medical Institute (M.N.), an EMBO Long-Term Fellowship (ALTF 7-2015), the European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409) and the Swiss National Science Foundation (P2ZHP3_158709) (O.M.).

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Author notes

    • Karen J. Mackenzie
    •  & Paula Carroll

    These authors contributed equally to this work.


  1. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK

    • Karen J. Mackenzie
    • , Paula Carroll
    • , Carol-Anne Martin
    • , Olga Murina
    • , Adeline Fluteau
    • , Daniel J. Simpson
    • , Nelly Olova
    • , Hannah Sutcliffe
    • , Jacqueline K. Rainger
    • , Andrea Leitch
    • , Ruby T. Osborn
    • , Ann P. Wheeler
    • , Nick Gilbert
    • , Tamir Chandra
    • , Martin A. M. Reijns
    •  & Andrew P. Jackson
  2. Laboratory of Protein Structure, International Institute of Molecular and Cell Biology, Warsaw, Poland

    • Marcin Nowotny


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K.J.M., P.C., M.A.M.R., C.-A.M., O.M., A.F., D.J.S., N.O., H.S., J.K.R., A.L., R.T.O., A.P.W., M.N. and N.G. performed experiments and analysed data. K.J.M., N.G., T.C., M.A.M.R. and A.P.J. planned the project and supervised experiments. M.A.M.R., K.J.M. and A.P.J. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Martin A. M. Reijns or Andrew P. Jackson.

Reviewer Information Nature thanks N. Gekara and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

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    Supplementary Information

    This file contains Supplementary Text, additional references, Supplementary table 1 and Supplementary Figure 1.

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    Reporting Summary


  1. 1.

    Live imaging of Rnaseh2b^-/- MEFs transiently expressing RFP-H2B

    Micronuclei form from lagging DNA and chromatin bridges occurring during mitosis in RNaseH2 deficient cells.

  2. 2.

    cGAS enters micronuclei after envelope rupture

    Live imaging of U2OS cells expressing mCherry-NLS and GFP-cGAS. DNA visualised with Hoechst.

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