title: A phylogenetically conserved DNA damage response resets the circadian clock.
abstract: The mammalian circadian clock influences the timing of many biological processes such as the sleep/wake cycle, metabolism, and cell division. Environmental cues such as light exposure can influence the timing of this system through the posttranslational modification of key components of the core molecular oscillator. We have previously shown that DNA damage can reset the circadian clock in a time-of-day-dependent manner in the filamentous fungus Neurospora crassa through the modulation of negative regulator FREQUENCY levels by PRD-4 (homologue of mammalian Chk2). We show that DNA damage, generated with either the radiomimetic drug methyl methane sulfonate or UV irradiation, in mouse embryonic fibroblasts isolated from PER2::LUC transgenic mice or in the NIH3T3 cell line, elicits similar responses. In addition to induction of phase advances, DNA damage caused a decrease in luciferase signal in PER2::LUC mouse embryonic fibroblast cells that is indicative of PER2 degradation. Finally, we show that the activity of the BMAL1 promoter is enhanced during DNA damage. These findings provide further evidence that the DNA damage-mediated response of the clock is conserved from lower eukaryotes to mammals.
authors.affiliation: Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755-3844, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Gamsby
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Loros
authors.forename: Jay C
authors.initials: JC
authors.lastname: Dunlap
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000502:physiology*; D005075:Biological Evolution; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D004249:DNA Damage; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens / Q000494:pharmacology; D041681:NIH 3T3 Cells / Q000187:drug effects / Q000528:radiation effects; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010802:Phylogeny; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D008741:Methyl Methanesulfonate; D009153:Mutagens; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse