Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes

Abstract

The circadian clock imparts 24-hour rhythmicity on gene expression and cellular physiology in virtually all cells. Disruption of the genes necessary for the circadian clock to function has diverse effects, including aging-related phenotypes. Some circadian clock genes have been described as tumor suppressors, while other genes have less clear functions in aging and cancer. In this Review, we highlight a recent study [Dubrovsky et al., Aging 2: 936-944, 2010] and discuss the much larger field examining the relationship between circadian clock genes, circadian rhythmicity, aging-related phenotypes, and cancer.

Figure 1.. Model illustrating the core transcriptional-translational feedback loop underlying circadian rhythmicity.

The components of the transcriptional activator complex, CLOCK, BMAL1, and (within SCN) NPAS2 form heterodimers that activate transcription of E-box containing genes, including the negative regulatory PER and CRY proteins. The PER-CRY protein complexes accumulate in the nucleus and block the activity of the activator complex. The alternation between the activation phase and the repression phase has a cycle length of near 24 hours. For simplicity, key events including posttranslational modifications and the generation of cascades of transcription factors leading to rhythmicity of tissue-specific “output” genes are not shown. For a more detailed model, see [2].

Figure 2.. Locomotor activity rhythms of circadian mutant mice.

Panels A-C, Double-plotted actograms illustrating types of locomotor activity patterns observed in wild-type and circadian mutant mice (see Tables 1 and 2). Each panel represents the locomotor activity pattern of a single mouse housed in a cage with a running wheel. Periods of voluntary wheel-running appear as dark bars within the grids. Each line of the record shows 48 hours of data across, and successive days are plotted below the first. Each animal was exposed to a standard 12 hour light: 12 hour dark lighting cycle (light period indicated by the yellow shading) for ~ 2 weeks. Then, the light-dark cycle was disabled and the animals were recorded in constant darkness (DD), which allows expression of the animals' endogenous rhythmicity. Visual analysis of the “actogram” allows easy perception of the cycle length (period length, represented by the slope of the line connecting activity onsets) and the robustness of the rhythm when the animal is in DD. (A) The actogram in Panel A is typical of a wild-type mouse. In the lighting cycle, activity is confined to the dark phase of the cycle. Upon entry into DD, the animal maintains robust rhythmicity with a cycle length of ~ 23.6 hours. This is seen as a leftward shift of activity onset each day by ~ 20 minutes. Lines of mice that would have similar activity records, with or without slight changes in circadian null mutations, CLOCK-deficient mice and NPAS2-deficient mice. Larger alterations in period length but with maintenance of robust rhythmicity is seen in CRY1-deficient mice, CRY2-deficient mice, and Clock Δ19/+ heterozygotes. (B) The actogram in Panel B is typical of a mouse with gradual loss of rhythmicity. The light-dark cycle synchronized activity to nighttime, and after transfer to DD, the animal expresses a “free-running” rhythm that gradually decreases in amplitude until arrhythmicity is reached. Mice homozygous for mutation of Per1 or Per2 have this phenotype (although in some studies these lines maintain rhythmicity and resemble Panel A). Clock^Δ19/Δ19 mutant mice initially have long-period (~ 28 hr) rhythmicity and become arrhythmic within ~ 10 days in constant darkness. (C) The actogram in Panel C is typical of an animal with complete loss of circadian function. Note that the mouse appears to have rhythmic behavior when exposed to a light-dark cycle, due to suppression of wheel-running activity by ambient light. Following discontinuation of the light-dark cycle, however, the endogenous pattern (or lack there-of) becomes apparent. In this case, the animal immediately loses circa-24-hour rhythmicity. Despite loss of circadian rhythmicity, the animal still has periods of activity and rest, just now these intervals do not have the temporal organization on a 24-hour timescale. Short-period rhythms (4-6 hr cycles) predominate. This pattern is typical of line of mice referred to as arrhythmic, including Clock/Npas2-double-knockout (Clock^−/−; Npas2^m/m) mice, Bmal1^−/− knockout, Per1/Per2 double knockout, and Cry1/Cry2 double-knockout mice.