Abstract
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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Change history
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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Acknowledgements
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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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.
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Rodier, F., Coppé, JP., Patil, C. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11, 973–979 (2009). https://doi.org/10.1038/ncb1909
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DOI: https://doi.org/10.1038/ncb1909
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