Abstract
Living in the earth’s oxygenated environment forced organisms to develop strategies to cope with the damaging effects of molecular oxygen known as reactive oxygen species (ROS). Here, we show that Per2, a molecular component of the mammalian circadian clock, is involved in regulating a cell’s response to oxidative stress. Mouse embryonic fibroblasts (MEFs) containing a mutation in the Per2 gene are more resistant to cytotoxic effects mediated by ROS than wild-type cells, which is paralleled by an altered regulation of bcl-2 expression in Per2 mutant MEFs. The elevated survival rate and alteration of NADH/NAD+ ratio in the mutant cells is reversed by introduction of the wild-type Per2 gene. Interestingly, clock synchronized cells display a time dependent sensitivity to paraquat, a ROS inducing agent. Our observations indicate that the circadian clock is involved in regulating the fate of a cell to survive or to die in response to oxidative stress, which could have implications for cancer development and the aging process.
Highlights
Life on earth is under the continuous influence of a light and dark cycle that is caused by the rotation of the earth around its axis and its orbit around the sun
The redox state of a cell has been proposed to be crucial for the regulation of clock gene dependent transcription via the NAD dependent enzyme SIRT1 [32, 33]
NADH favors formation of heterodimers between CLOCK or NPAS2 with BMAL1, which bind to DNA at E-box promoter elements, regulating the efficiency with which many circadian clock and clock controlled genes are transcribed
Summary
Life on earth is under the continuous influence of a light and dark cycle that is caused by the rotation of the earth around its axis and its orbit around the sun. The positive limb involves CLOCK:BMAL1 heterodimers that bind to E-box promoter elements located in the regulatory region of the Period (Per, Per2) and Cryptochrome (Cry, Cry2) genes Their proteins form oligomers that are transported from the cytoplasm to the nucleus where they repress their own transcription (negative limb) [5]. One could expect that an organism with a defective circadian clock would have difficulties in coping with environmental stress This view is supported by the finding that mice mutant in the Per gene [Per2Brdm, Ref. [9]] are cancer-prone after γ irradiation [10] The effects of this DNA damaging treatment might be related to abnormal responses of Per2Brdm mutant cells to oxidative stress. We found that at the cellular level Per is involved in the response of a cell to oxidative stress
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