DNA-Damage-Induced Type I Interferon Promotes Senescence and Inhibits Stem Cell Function

• Cells undergoing DNA damage induce endogenous IFN-β production
• A cell-autonomous ATM, IKKα/β, and IRF3-dependent pathway is involved
• IFN-β amplifies DNA-damage response and induces cellular senescence
• IFN-β mediates accelerated senescence in mice with shortened telomeres

SummaryExpression of type I interferons (IFNs) can be induced by DNA-damaging agents, but the mechanisms and significance of this regulation are not completely understood. We found that the transcription factor IRF3, activated in an ATM-IKKα/β-dependent manner, stimulates cell-autonomous IFN-β expression in response to double-stranded DNA breaks. Cells and tissues with accumulating DNA damage produce endogenous IFN-β and stimulate IFN signaling in vitro and in vivo. In turn, IFN acts to amplify DNA-damage responses, activate the p53 pathway, promote senescence, and inhibit stem cell function in response to telomere shortening. Inactivation of the IFN pathway abrogates the development of diverse progeric phenotypes and extends the lifespan of Terc knockout mice. These data identify DNA-damage-response-induced IFN signaling as a critical mechanism that links accumulating DNA damage with senescence and premature aging.

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