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.

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