Effect of circadian clock mutations on DNA damage response in mammalian cells

Abstract

The circadian clock is a global regulatory mechanism that confers daily rhythmicity on many biochemical and physiological functions, including DNA excision repair in mammalian organisms. Here, we investigated the effect of the circadian clock on the major DNA damage response pathways by using mouse cell lines mutated in genes encoding proteins in the positive (Bmal1, CLOCK) or negative (Cry 1/2, Per 1/2) arms of the transcription-translation feedback loop that generates the circadian clock. We find that cells mutated in these genes are indistinguishable from wild-type in their response to UV, ionizing radiation and mitomycin C. We conclude that either the majority of DNA damage response reactions are not controlled by the circadian clock or that, even if such a control exists at the organism level, it is supplanted by homeostatic control mechanisms at the cellular level in tissue culture. We suggest that caution must be exercised in extrapolating from experiments in tissue culture to whole animals with respect to the effect of the circadian clock on cellular response to DNA damaging agents.

Keywords: :

• Cryptochrome
• Period
• Clock
• BMal1
• DNA repair
• checkpoint
• apoptosis

This article is referred to by:

Cell-autonomous circadian DNA damage response

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Dr. M.P. Antoch and Dr. C.C. Lee for providing the Primary MEFs from wild-type, Bmal^−/− and Clock^−/− mice and Per1/2^−/− mouse, respectively. This work was supported by National Institutes of Health grants (GM31082 and GM32833) to A.S.