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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.

SUBMITTER: Gaddameedhi S

PROVIDER: S-EPMC3466558 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Gaddameedhi Shobhan S Reardon Joyce T JT Ye Rui R Ozturk Nuri N Sancar Aziz A

Cell cycle (Georgetown, Tex.) 20120823 18

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 f ...[more]

PMID: 22918252

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Project description:PurposeMice lacking rods and cones retain pupillary light reflexes that are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin is necessary and sufficient for this nonvisual photoreception. The mammalian inner retina also expresses the potential blue light photopigments cryptochromes 1 and 2. Previous studies have shown that outer retinal degenerate mice lacking cryptochromes have lower nonvisual photic sensitivity than retinal degenerate mice, suggesting a role for cryptochrome in inner retinal photoreception.MethodsNonvisual photoreception (pupillary light responses, circadian entrainment, and in vitro sensitivity of intrinsically photosensitive retinal ganglion cells) were studied in wild-type, rd/rd, and circadian clock-mutant mice with and without rd/rd mutation.ResultsLoss of cryptochrome in retinal degenerate mice reduces the sensitivity of the pupillary light response at all wavelengths but does not alter the form of the action spectrum, suggesting that cryptochrome does not function as a photopigment in the inner retina. The authors compounded the rd/rd retinal degeneration mutation with mutations in other essential circadian clock genes, mPeriod and Bmal1. Both mPeriod1?/?; mPeriod2?/?;rd/rd and Bmal1?/?;rd/rd mice showed significantly lower pupillary light sensitivity than rd/rd mice alone. A moderate amplitude (0.5 log) circadian rhythm of pupillary light responsiveness was observed in rd/rd mice. Multielectrode array recordings of ipRGC responses of mCryptochrome1?/?;mCryptochrome2?/? and mPeriod1?/?;mPeriod2?/? mice showed minimal sensitivity decrement compared with wild-type animals. mCryptochrome1?/?;mCryptochrome2?/?;rd/rd, mPeriod1?/?;mPeriod2?/?;rd/rd and Bmal1?/?;rd/rd mice all showed comparable weak behavioral synchronization to a 12-hour light/12-hour dark cycle.ConclusionsThe effect of cryptochrome loss on nonvisual photoreception is due to loss of the circadian clock nonspecifically. The circadian clock modulates the sensitivity of nonvisual photoreception.

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

Publications

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

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