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Journal of Biological Rhythms
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A Phylogenetically Conserved DNA Damage Response Resets the Circadian Clock

Joshua J. Gamsby

Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire

Jennifer J. Loros

Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire

Jay C. Dunlap

Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, Jay.C.Dunlap{at}dartmouth.edu

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.

Key Words: circadian • DNA damage • phase-response curve • Per2 • BMAL1 • luciferase

Journal of Biological Rhythms, Vol. 24, No. 3, 193-202 (2009)
DOI: 10.1177/0748730409334748
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