When cells are exposed to a serious insult, such as ionizing radiation, which causes DNA double-strand breaks (DSBs), they become senescent, a state of arrested cellular proliferation that opposes the development of cancer. Such cells exhibit a senescence-associated secretory phenotype (SASP), which is characterized by the release of factors, such as the proinflammatory cytokine interleukin-6 (IL-6), that reinforce senescence, but can also paradoxically trigger the proliferation of surrounding cells to form tumors. To investigate the mechanisms that trigger the SASP, Rodier et al. studied the effects of low-dose or high-dose x-ray irradiation on human fibroblasts and found that although low doses of radiation resulted in transient DNA DSBs, SASP was not stimulated. In contrast, high-dose radiation led to the formation of persistent DNA damage foci and the onset of the SASP, as determined by measurement of secreted IL-6. Expression of p16, an inhibitor of cyclin-dependent kinase that induces cellular senescence without causing DNA DSBs, failed to trigger the SASP, whereas other agents that trigger the DNA damage response (DDR) stimulated the SASP. Knockdown of various components of the DDR, including the kinase ATM (ataxia telangiectasia mutated), blocked the secretion of some, but not all, of the factors characteristic of the SASP, whereas knockdown of p53, which arrests cellular proliferation during the DDR, had no effect on the SASP. ATM was also required for the secretion of IL-6 in response to oncogene-induced senescence, which also involves the DDR. As Fumagalli and di Fagagna discuss, these findings link ATM and other early components of the DDR with inflammation and potentially with tumor development, links that may provide therapeutic targets.
F. Rodier, J.-P. Coppé, C. K. Patil, W. A. M. Hoeijmakers, D. P. Muñoz, S. R. Raza, A. Freund, E. Campeau, A. R. Davalos, J. Campisi, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). [PubMed]
M. Fumagalli, F. d’Adda di Fagagna, SASPense and DDRama in cancer and ageing. Nat. Cell Biol. 11, 921–923 (2009). [PubMed]