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Phase resetting of the mammalian circadian clock by DNA damage

Małgorzata Oklejewicz1, Eugin Destici, Filippo Tamanini

  • 1Department of Genetics, Erasmus University Medical Center, 3000CA Rotterdam, The Netherlands.

Current Biology : CB
|February 23, 2008
PubMed

Insights

DNA damage, including ionizing radiation, can phase advance the internal biological clock. This effect is mediated by ATM signaling and observed in both cell cultures and living animals, suggesting a universal response.

Area of Science:

  • Chronobiology
  • Molecular Biology
  • Genetics

Background:

  • Organisms possess internal clocks regulating circadian rhythms in metabolism, physiology, and behavior.
  • Cell-cycle progression and DNA-damage response pathways are influenced by circadian control.
  • The feedback of circadian output processes on the clock necessitates investigation into DNA damage effects.

Purpose of the Study:

  • To investigate whether DNA damage affects the mammalian circadian clock.
  • To elucidate the mechanism underlying DNA damage-induced circadian clock resetting.

Main Methods:

  • Utilized Rat-1 fibroblasts with an mPer2 promoter-driven luciferase reporter to assess circadian rhythm phase shifts.
  • Exposed cells and live mice to ionizing radiation to observe effects on circadian rhythms.
  • Investigated the role of ATM-mediated damage signaling using fibroblasts from relevant patient groups.
  • Tested the effects of ultraviolet light and tert-butyl hydroperoxide on circadian rhythms.

Main Results:

  • Ionizing radiation caused a dose- and time-dependent phase advance of circadian rhythms in fibroblasts.
  • This phase-advancing effect was replicated in the behavioral rhythms of mice.
  • Radiation-induced phase shifting was suppressed in ataxia telangiectasia and Nijmegen breakage syndrome patient fibroblasts, indicating ATM-mediated signaling.
  • The mechanism did not involve changes in clock gene expression or de novo protein synthesis.

Conclusions:

  • The mammalian circadian clock responds to DNA damage, specifically exhibiting phase advancement.
  • ATM-mediated signaling is crucial for radiation-induced circadian clock resetting.
  • Clock resetting in response to DNA damage appears to be a universal biological property.

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