Persistent DNA damage signaling triggers the secretion of inflammatory cytokines associated with cellular senescence. This study shows that damaged human cells develop persistent chromatin lesions resembling DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurs only after the establishment of persistent DNA damage signaling, not after transient DNA damage responses. The initiation and maintenance of this cytokine response require DNA damage response (DDR) proteins ATM, NBS1, and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM is essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. DDR activity and IL-6 levels are elevated in human cancers, and ATM depletion suppresses the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, the DDR has a novel and important role in allowing damaged cells to communicate their compromised state to the surrounding tissue. Cellular senescence limits the proliferation of damaged cells at risk for neoplastic transformation by imposing an essentially irreversible growth arrest. Senescent cells also develop a complex senescence-associated secretory phenotype (SASP), which can disrupt normal mammary differentiation, promote endothelial cell invasion, and stimulate cancer cell growth and invasion. Among the SASP factors, IL-6 and IL-8 are of particular interest as they initiate inflammatory responses and are associated with many age-related pathologies, including cancer. DNA damage triggers DDR signaling, which is essential for the secretion of inflammatory cytokines. The DDR proteins ATM, NBS1, and CHK2 are required for the secretion of IL-6, while p53 and pRb are not. ATM is essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. DDR activity and IL-6 levels are elevated in human cancers, and ATM depletion suppresses the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. The study also shows that DDR signaling drives a subset of SASP factors, including the potent inflammatory cytokines IL-6 and IL-8. IL-6 is particularly important for the ability of senescent cells to promote cancer cell invasion. Persistent DNA damage is seen in premalignant and malignant lesions, which are presumed to harbor activated oncogenes. The study suggests that DDR signaling drives the inflammation that is also a hallmark of premalignant, malignant, and aging tissues. During aging, damaged cells might cause or contribute to tissue dysfunction, including dysfunctional stem cell niches. In cancer, such cells might promote inflammation, angiogenesis, or other phenotypes of cancer progression. The study identifies a novel response to persistent DNA damage – the secretion of factors that allow damaged cells toPersistent DNA damage signaling triggers the secretion of inflammatory cytokines associated with cellular senescence. This study shows that damaged human cells develop persistent chromatin lesions resembling DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurs only after the establishment of persistent DNA damage signaling, not after transient DNA damage responses. The initiation and maintenance of this cytokine response require DNA damage response (DDR) proteins ATM, NBS1, and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM is essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. DDR activity and IL-6 levels are elevated in human cancers, and ATM depletion suppresses the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, the DDR has a novel and important role in allowing damaged cells to communicate their compromised state to the surrounding tissue. Cellular senescence limits the proliferation of damaged cells at risk for neoplastic transformation by imposing an essentially irreversible growth arrest. Senescent cells also develop a complex senescence-associated secretory phenotype (SASP), which can disrupt normal mammary differentiation, promote endothelial cell invasion, and stimulate cancer cell growth and invasion. Among the SASP factors, IL-6 and IL-8 are of particular interest as they initiate inflammatory responses and are associated with many age-related pathologies, including cancer. DNA damage triggers DDR signaling, which is essential for the secretion of inflammatory cytokines. The DDR proteins ATM, NBS1, and CHK2 are required for the secretion of IL-6, while p53 and pRb are not. ATM is essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. DDR activity and IL-6 levels are elevated in human cancers, and ATM depletion suppresses the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. The study also shows that DDR signaling drives a subset of SASP factors, including the potent inflammatory cytokines IL-6 and IL-8. IL-6 is particularly important for the ability of senescent cells to promote cancer cell invasion. Persistent DNA damage is seen in premalignant and malignant lesions, which are presumed to harbor activated oncogenes. The study suggests that DDR signaling drives the inflammation that is also a hallmark of premalignant, malignant, and aging tissues. During aging, damaged cells might cause or contribute to tissue dysfunction, including dysfunctional stem cell niches. In cancer, such cells might promote inflammation, angiogenesis, or other phenotypes of cancer progression. The study identifies a novel response to persistent DNA damage – the secretion of factors that allow damaged cells to