Faculty Opinions recommendation of Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.
Year: 2009
Type: peer-review
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 signaling, usually associated with senescence, not after transient DNA damage responses (DDR).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.Further, 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 novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.Cellular senescence limits the proliferation of damaged cells that are at risk for neoplastic transformation by imposing an essentially irreversible growth arrest1.Senescent cells also develop a complex senescence-associated secretory phenotype (SASP), in culture and in vivo3-6.The SASP can disrupt normal mammary differentiation4,7, promote endothelial cell invasion8, and stimulate cancer cell growth and invasion in culture and tumor growth in vivo4-6.Additionally, some SASP factors can reinforce the senescence arrest by autocrine or paracrine mechanisms9-12.Among the SASP factors, IL-6 and IL-8 are of particular Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.
Authors: Ashani Weeraratna, Mai Xu
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4206468107