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Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion

Nature Cell Biology volume 11, pages 973979 (2009) | Download Citation

  • An Erratum to this article was published on 01 October 2009

This article has been updated


Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Furthermore, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.

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  • 24 August 2009

    In the version of this article initially published, the labelling of the radiation doses in Fig. 1a was reversed. These errors have been corrected in the HTML and PDF versions of the article.


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We thank C. Beausejour (grant CIHR # MPO-79317) for help in the design of a modified lentiviral expression system, R. Teachenor, V. Chu and G. Tang for valuable technical assistance, and P. Desprez for insightful comments on the manuscript. This work was supported by National Institutes of Health grants AG017242 (J.C.) and AG025708 (Buck Institute), a CABCRP grant 11IB-0153 (A.R.D.), a Larry L. Hillblom Foundation fellowship (C.K.P.), the Netherlands Organization for International Cooperation in Higher Education (Nuffic, HSP-TP 06/78), the Dutch Cancer Society (W.A.M.H.), and the Department of Energy under contract DE-AC03-76SF00098 to the University of California.

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Author notes

    • Wieteke A. M. Hoeijmakers

    Current address: Department of Molecular Biology, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.

    • Saba R. Raza

    Current address: Royal Free & University College Medical School, Gower Street, London WC1E 6BT, UK.

    • Eric Campeau

    Current address: Program in Gene Function and Expression, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.


  1. Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA.

    • Francis Rodier
    • , Jean-Philippe Coppé
    • , Christopher K. Patil
    • , Wieteke A. M. Hoeijmakers
    • , Saba R. Raza
    • , Adam Freund
    • , Eric Campeau
    • , Albert R. Davalos
    •  & Judith Campisi
  2. Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94545, USA.

    • Francis Rodier
    • , Denise P. Muñoz
    •  & Judith Campisi
  3. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.

    • Adam Freund


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F.R. designed, performed and analysed the experiments; J.P.C. and C.K.P. performed antibody arrays; J.P.C. and W.A.M.H. performed ELISAs; S.R.R. analysed immunofluorescence; A.F. analysed tissue arrays, A.R.D.; DPM and E.C. generated and tested p53 and ATM RNAi constructs; J.C. analysed data and F.R. and J.C. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Judith Campisi.

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