Circadian tempo: A paradigm for genome stability?

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Summary

Circadian clocks are molecular time-keeping systems that underlie daily biological rhythms in anticipation of the changing light and dark cycles. These clocks mediate daily rhythms in physiology and behavior that are thought to confer an adaptive advantage for organisms. It is hypothesized that cell cycle checkpoints are gated to an intrinsic circadian clock to protect DNA from diurnal exposure to mutagens (e.g.; UV radiation peaks with daylight and dissolved genotoxins that fluctuate with feeding periods). It is proposed that DNA replication arrest in response to genotoxic stress is a likely basis for the evolution of circadian-gated DNA replication. This protective mechanism is highly conserved and can be traced along the evolutionary time-line to the early prokaryotes, unicellular eukaryotes and viruses. Peak DNA repair capacity is normally synchronous to the crest of mutagenic stress as they oscillate with respect to time. Mutator phenotypes with increased vulnerability to genotoxic stress may therefore develop when the circadian pattern of cell cycle control, DNA repair or apoptotic response are phase-shifted relative to the rhythm of mutagenic stress. The accumulating mutations would lead to accelerated aging, genome instability and neoplasia. The proposed model delineates areas of research with potentially profound implications for carcinogenesis.

Introduction

Circadian clocks are endogenous time-keeping systems that underlie the daily biological rhythms of organisms [1], [2], [3], [4]. These autoregulatory oscillations are generated by transcriptional/translational feedback loops that are reset by external time cues, and in particular, the light and dark cycle. These in turn regulate the rhythm of cellular proliferation, differentiation and DNA repair [4], [5], [6], [7]. Circadian regulation can be traced back along the phylogenetic time-line to early prokaryotes and unicellular eukaryotes [8]. Circadian timing has been implicated in the rhythmic regulation of morphogenesis and organogenesis in multicellular organisms [9], [10]. Adaptation of early unicellular organisms to the light–dark cycle may have evolved to minimize exposure to diurnal onslaught of environmental radiation and related DNA damage (Fig. 1A).

Regulation of cell cycle appears to be synchronized to a circadian pattern. Cellular proliferation, differentiation, DNA repair, and apoptosis seem to be regulated by genes that are expressed in a circadian fashion, and control cell cycle check points to preserve genome integrity [11], [12], [13]. Key output genes of the circadian clock (also called clock control genes) regulate the cell cycle, tumor suppressor genes, and DNA repair pathways [5], [14], [15], [16]. It is proposed here that aberrations in the expression of the circadian-controlled cell-cycle genes could disrupt normal cellular processes, causing accumulation of mutations, accelerated aging, and development of a “mutator phenotype” (Fig. 1C and D).

Section snippets

The circadian clock is highly conserved

The circadian clock developed early in the evolution of life presumably to enable organisms adapt to the cycle of day and night. The origin and evolution of circadian clock genes in prokaryotes has been described in cyanobacteria [8], [17]. Elements of the circadian clock have been conserved among such diverse organisms as algae, cockroach, Drosophila, avian species and mammals [18], [19], [20], [21]. PAS domain containing proteins play a key role in each of these systems.

The cell cycle is regulated by the circadian clock

The cell cycle is regulated by an endogenous programmable cellular clock that generates circadian periodicity [7]. Cell proliferation is regulated by circadian clock-controlled genes [22], [23], [24]. Human epidermal cells follow a diurnal pattern of periodic entrance from G1 into the S-phase [25]. S-phase variations occur according to circadian stage, with higher levels of synthesis noted in the 8 p.m. to 8 a.m. interval [26]. Expression of the p53 tumor suppressor gene and the oncogene Bcl-2

Circadian control of the cell cycle may have evolved due to a necessity to protect DNA against radiation

The circadian clock may have developed early in evolution to enable adaptation of cells to cycles of light and dark (Fig. 1). Adaptation to the light cycle requires an ability to predict the presence of light and protect the cell against ionizing radiation (Fig. 1A). Cell cycle arrest at checkpoint controls may have evolved to protect DNA against ionizing radiation from sun light. It is plausible that cell cycle arrest in response to DNA damage, and the circadian regulation of the cell cycle

DNA repair pathways may have evolved in adaptation to diurnal radiation

It has been suggested that the UV component of sunlight provided a strong selective pressure for the evolution of the circadian photoreceptor cryptochrome from the DNA repair enzymes (photolyases) [47]. These enzymes reverse UV-induced mutations by a light-dependent mechanism [48]. Most bacteria have a photolyase or a photolyase-like gene [48]. Homologs of photolyases have been identified in higher eukaryotes. These are termed cryptochromes and in plants and flies function as blue-light

P53 Links the cell cycle to the circadian pathway

P53 plays a central role in the protection of the genome against genotoxic stress from multiple endogenous and environmental insults [63]. UV or gamma irradiation-mediated DNA damage activates p53. In addition to induction of DNA repair pathways, p53 seems to protect the genome by linking the cell cycle to the circadian pathway. The resulting synchrony limits exposure to diurnal radiation to the periods when DNA repair is optimal (Fig. 1B). P53 expression fluctuates according to a circadian

Circadian-gated cell cycle in multicellular organisms: protection against diurnal genotoxic stress

Multicellular organisms need to protect DNA against radiation as well as from chemical mutagens in solution. Exposure to ingested mutagens is dependent upon environmental and behavioral factors (e.g.; eating patterns). The timing of the cell cycle and DNA repair in relationship to the peak of genotoxic stress is likely to be specific to individual tissues. Multicellular organisms may require to partition circadian clock function [65] according to the exposure pattern of individual tissues to

Apoptosis is potentially clock regulated

Apoptotic cell death has been noted to occur in a circadian pattern in the tongue, epidermis, and intestinal epithelia [81]. Apoptosis in the rat intestine is coincident with the cessation of feeding [82], suggesting that postprandial factors are important in the diurnal regulation of apoptosis [83]. Diurnal variation in the occurrence of apoptosis has been described in the small intestine and colonic epithelia of mice challenged with gama-irradiation and chemical carcinogens [84], [85], [86].

Components of the circadian clock regulate ontogeny and tissue development

Ontogeny is regulated by components of the circadian clock. During embryogenesis cells undergo critically timed developmental commitments [89]. A circadian oscillator involving the clock gene Per3 is identified during early development of zebrafish [90]. Differential expression patterns for Per2 and Per3 suggest specific roles in the establishment of the embryonic circadian system [91]. Developmental timing in Caenorhabditis elegans is regulated by kin-20 and Tim-1, two homologs of core

Uncoupling of circadian gene expression from the cell cycle leads to genome instability, premature aging and cancer: knock-out studies

Loss of function mutations in circadian genes resulted in death following sleep deprivation in Drosophila [105]. Death is preventable in Drosophila mutants by activation of heat-shock genes [105]: these are highly conserved and guard against genomic instability as shown in knockout mice [106]. Mice deficient in the circadian gene Per2 accumulate mutations, age prematurely and are prone to neoplastic growth [106]. Genetic lesions accumulate with accelerated senescence in knockout mice deficient

Circadian pattern of cell cycle gene expression is “phase-shifted” in neoplastic cells

Neoplastic cells exhibit circadian patterns of gene expression that are “phase-shifted” relative to normal cells (Fig. 1). In mammary adenocarcinoma, the circadian organization in cell-cycle phase distribution is altered and the rhythmic expression of the BCL2 oncogene is lost [11]. Even though proliferating tumor cells show autonomous circadian patterns, these are not in phase with the patterns noted in normal cells [120]. DNA synthesis rhythm in healthy cells is often in “phase-dissociation”

Molecular genetics links circadian genes to carcinogenesis

Disruption of circadian gene expression is a risk factor for breast cancer, endometrial cancer, and leukemia. Over 95% of breast cancer cells exhibit disturbances in the expression of Per1, Per2, and Per3 genes [14]. Per gene deregulation appears to be due to methylation of the promoter sites rather than from genetic mutations [14]. Methylation of Per gene promoters correlate strongly with expression of the c-erB2 gene [14]. A variant of Per3 genotype is associated with increased risk of breast

Cautious interpretation of the evidence is needed

By definition a 24 h oscillation should occur in the absence of external cues such as light for a given purely circadian process. Many of the experiments discussed, need to be performed under constant darkness or light. Core clock components like Clock or Bmal regulate more non-clock genes than clock output genes. Cellular physiology may therefore be altered in a clock-mutant model, with a deficiency in oscillator function, even though this alteration is unrelated to the clock. Cautious

Conclusions

It is proposed that the circadian system likely developed early in evolution to protect cells against ionizing radiation. Cell cycle arrest at checkpoint controls in response to DNA damage, and the circadian regulation of the cell cycle are linked and perhaps evolved in adaptation to diurnal radiation exposure. Intracellular disruption of the circadian pathway may result in genome instability, rapid aging, and carcinogenesis.

In certain conditions (e.g., mutations, hormonal changes, circadian

Acknowledgements

I am grateful to Dr. John Hogenesch for his thoughtful editing and comments on the circadian sections. Gratitude is expressed to Drs. Daniel F. Kripke and Stephen F. Johnson for their interest and helpful comments on the manuscript.

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