Letter abstract

Nature Cell Biology 11, 973 - 979 (2009)
Published online: 13 July 2009 | Corrected online: 24 August 2009 | doi:10.1038/ncb1909



There is an Erratum (October 2009) associated with this Letter.

Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion

Francis Rodier1,2, Jean-Philippe Coppé1, Christopher K. Patil1, Wieteke A. M. Hoeijmakers1,4, Denise P. Muñoz2, Saba R. Raza1,5, Adam Freund1,3, Eric Campeau1,6, Albert R. Davalos1 & Judith Campisi1,2

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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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  1. Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA.
  2. Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94545, USA.
  3. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
  4. Current address: Department of Molecular Biology, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
  5. Current address: Royal Free & University College Medical School, Gower Street, London WC1E 6BT, UK.
  6. Current address: Program in Gene Function and Expression, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.

Correspondence to: Judith Campisi1,2 e-mail: jcampisi@lbl.gov.

* 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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