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Cell Rep. 2015 May 5;11(5):785-797. doi: 10.1016/j.celrep.2015.03.069. Epub 2015 Apr 23.

DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function.

Author information

1
Department of Animal Biology, School of Veterinary Medicine, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 380 S. University Ave, Philadelphia, PA 19104, USA.
2
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 380 S. University Ave, Philadelphia, PA 19104, USA.
3
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 380 S. University Ave, Philadelphia, PA 19104, USA.
#
Contributed equally

Abstract

Expression 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.

PMID:
25921537
PMCID:
PMC4426031
DOI:
10.1016/j.celrep.2015.03.069
[Indexed for MEDLINE]
Free PMC Article

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