DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function.
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.
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.
Qiujing
Q
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 Ave, Philadelphia, PA 19104, USA.
Yuliya V
YV
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 Ave, Philadelphia, PA 19104, USA.
Christopher J
CJ
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 Ave, Philadelphia, PA 19104, USA.
Bin
B
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 Ave, Philadelphia, PA 19104, USA.
Kanstantsin V
KV
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 Ave, Philadelphia, PA 19104, USA.
Hui
H
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 Ave, Philadelphia, PA 19104, USA.
Manti
M
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 Ave, Philadelphia, PA 19104, USA.
Ning
N
Li
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.
Qijun
Q
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 Ave, Philadelphia, PA 19104, USA.
Ting
T
Yang
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.
Christopher J
CJ
Lengner
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.|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.
Roger A
RA
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 Ave, Philadelphia, PA 19104, USA.
F Brad
FB
Johnson
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.
Serge Y
SY
Fuchs
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D016922:Cellular Senescence; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; C508032:Ifnar1 protein, mouse; D050838:Interferon Regulatory Factor-3; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D053633:Receptor, Interferon alpha-beta; C016601:afimoxifene; D016899:Interferon-beta; D019098:Telomerase