title: Phase resetting of the mammalian circadian clock by DNA damage.
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.
authors.affiliation: Department of Genetics, Erasmus University Medical Center, 3000CA Rotterdam, The Netherlands.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Oklejewicz
authors.forename: Eugin
authors.initials: E
authors.lastname: Destici
authors.forename: Filippo
authors.initials: F
authors.lastname: Tamanini
authors.forename: Roelof A
authors.initials: RA
authors.lastname: Hut
authors.forename: Roel
authors.initials: R
authors.lastname: Janssens
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: 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
chemical_list: 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