Phase resetting of the mammalian circadian clock by DNA damage.
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.
Oklejewicz
Małgorzata
M
Department of Genetics, Erasmus University Medical Center, 3000CA Rotterdam, The Netherlands.
Destici
Eugin
E
Tamanini
Filippo
F
Hut
Roelof A
RA
Janssens
Roel
R
van der Horst
Gijsbertus T J
GT
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002940:Circadian Rhythm / Q000187:drug effects / Q000528:radiation effects*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D005720:Gamma Rays / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases