Abstract
Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Western
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line
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Cells, Cultured
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Cellular Senescence / physiology*
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Checkpoint Kinase 2
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cytokines / metabolism*
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DNA Damage*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enzyme-Linked Immunosorbent Assay
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Fibroblasts / radiation effects
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Interleukin-6 / metabolism
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Male
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Microscopy, Fluorescence
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / genetics
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Signal Transduction / physiology*
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Telomerase / genetics
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Telomerase / metabolism
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Telomere / genetics
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Transfection
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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Cytokines
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DNA-Binding Proteins
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Interleukin-6
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NBN protein, human
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Nuclear Proteins
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Green Fluorescent Proteins
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Checkpoint Kinase 2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK2 protein, human
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Protein Serine-Threonine Kinases
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TERT protein, human
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Telomerase