DNA-Damage-Induced Type I Interferon Promotes Senescence and Inhibits Stem Cell Function
Qiujing Yu,
Yuliya V. Katlinskaya,
Christopher J. Carbone,
Bin Zhao,
Kanstantsin V. Katlinski,
Hui Zheng,
Manti Guha,
Ning Li,
Qijun Chen,
Ting Yang,
Christopher J. Lengner,
Roger A. Greenberg,
F. Brad Johnson,
Serge Y. Fuchs
Affiliations
Qiujing Yu
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 Avenue, Philadelphia, PA 19104, USA
Yuliya V. Katlinskaya
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 Avenue, Philadelphia, PA 19104, USA
Christopher J. Carbone
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 Avenue, Philadelphia, PA 19104, USA
Bin Zhao
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 Avenue, Philadelphia, PA 19104, USA
Kanstantsin V. Katlinski
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 Avenue, Philadelphia, PA 19104, USA
Hui Zheng
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 Avenue, Philadelphia, PA 19104, USA
Manti Guha
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 Avenue, Philadelphia, PA 19104, USA
Ning Li
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 Avenue, Philadelphia, PA 19104, USA
Qijun Chen
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 Avenue, Philadelphia, PA 19104, USA
Ting Yang
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 Avenue, Philadelphia, PA 19104, USA
Christopher J. Lengner
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 Avenue, Philadelphia, PA 19104, USA
Roger A. Greenberg
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 Avenue, Philadelphia, PA 19104, USA
F. Brad Johnson
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 Avenue, Philadelphia, PA 19104, USA
Serge Y. Fuchs
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 Avenue, Philadelphia, PA 19104, USA
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.
