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

doi:10.1016/j.celrep.2015.03.069

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antibodies, Neutralizing / immunology
Antineoplastic Agents / pharmacology
Apoptosis
Cell Line
Cellular Senescence*
DNA Damage* / drug effects
Humans
Interferon Regulatory Factor-3 / antagonists & inhibitors
Interferon Regulatory Factor-3 / genetics
Interferon Regulatory Factor-3 / metabolism
Interferon-beta / antagonists & inhibitors
Interferon-beta / genetics
Interferon-beta / metabolism*
Intestinal Mucosa / metabolism
Intestines / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NIH 3T3 Cells
RNA Interference
RNA, Messenger / metabolism
Receptor, Interferon alpha-beta / deficiency
Receptor, Interferon alpha-beta / genetics
Receptor, Interferon alpha-beta / metabolism
Signal Transduction
Stem Cells / cytology
Stem Cells / metabolism
Tamoxifen / analogs & derivatives
Tamoxifen / pharmacology
Telomerase / deficiency
Telomerase / genetics
Telomerase / metabolism
Telomere / metabolism
Tumor Suppressor Protein p53 / metabolism

Substances

Antibodies, Neutralizing
Antineoplastic Agents
Ifnar1 protein, mouse
Interferon Regulatory Factor-3
RNA, Messenger
Tumor Suppressor Protein p53
Tamoxifen
Receptor, Interferon alpha-beta
afimoxifene
Interferon-beta
Telomerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding