The study investigates the role of persistent DNA damage signaling in triggering senescence-associated inflammatory cytokine secretion. The authors found 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). This cytokine secretion occurs only after the establishment of persistent DNA damage signaling, typically associated with senescence, and not after transient DNA damage responses (DDR). The initiation and maintenance of this cytokine response required 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. Additionally, DDR activity and IL-6 levels were elevated in human cancers, and ATM depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. These findings suggest that a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue, contributing to the SASP and potentially influencing cancer progression and tissue dysfunction.The study investigates the role of persistent DNA damage signaling in triggering senescence-associated inflammatory cytokine secretion. The authors found 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). This cytokine secretion occurs only after the establishment of persistent DNA damage signaling, typically associated with senescence, and not after transient DNA damage responses (DDR). The initiation and maintenance of this cytokine response required 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. Additionally, DDR activity and IL-6 levels were elevated in human cancers, and ATM depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. These findings suggest that a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue, contributing to the SASP and potentially influencing cancer progression and tissue dysfunction.