Phase resetting of the mammalian circadian clock by DNA damage

Curr Biol. 2008 Feb 26;18(4):286-91. doi: 10.1016/j.cub.2008.01.047.

Abstract

To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior [1]. Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are under circadian control [2-4]. Because circadian output processes can feed back into the clock, we investigated whether DNA damage affects the mammalian circadian clock. By using Rat-1 fibroblasts expressing an mPer2 promoter-driven luciferase reporter, we show that ionizing radiation exclusively phase advances circadian rhythms in a dose- and time-dependent manner. Notably, this in vitro finding translates to the living animal, because ionizing radiation also phase advanced behavioral rhythms in mice. The underlying mechanism involves ATM-mediated damage signaling as radiation-induced phase shifting was suppressed in fibroblasts from cancer-predisposed ataxia telangiectasia and Nijmegen breakage syndrome patients. Ionizing radiation-induced phase shifting depends on neither upregulation or downregulation of clock gene expression nor on de novo protein synthesis and, thus, differs mechanistically from dexamethasone- and forskolin-provoked clock resetting [5]. Interestingly, ultraviolet light and tert-butyl hydroperoxide also elicited a phase-advancing effect. Taken together, our data provide evidence that the mammalian circadian clock, like that of the lower eukaryote Neurospora[6], responds to DNA damage and suggest that clock resetting is a universal property of DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Biological Clocks / drug effects
  • Biological Clocks / genetics
  • Biological Clocks / radiation effects*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / radiation effects*
  • DNA Damage*
  • DNA-Binding Proteins / metabolism
  • Gamma Rays / adverse effects
  • Gene Expression / drug effects
  • Gene Expression / radiation effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Signal Transduction / radiation effects
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases