Circadian regulation of cell cycle: Molecular connections between aging and the circadian clock

Figures & data

Figure 1. Overview of the positive and negative transcriptional–translational feedback loops controlling the circadian machinery. BMAL1 and CLOCK proteins heterodimerize and drive the expression of the target genes Pers, Crys, Decs, Rev-Erbα, and RORs through binding to the circadian E box element in their promoters. PERs and CRYs form a complex which inhibits the BMAL1:CLOCK complex transcriptional activity, and hence their own expression. The nuclear receptor REV-ERBα represses and the retinoid-related orphan receptor ROR promotes the transcription of BMAL1 though binding to ROR elements in the Bmal1 promoter (2). DECs compete with the BMAL1:CLOCK complex at the E box located in the DEC promoter and so inhibit their own transcription. The BMAL1:CLOCK complex also regulates the expression of various clock-controlled genes (CCGs), which play important roles in many physiological functions.

Figure 2. Control of cell death and proliferation by the circadian clock transcriptional complex. All circadian clock proteins are shown in bold, direct transcriptional control is shown by thick arrows, transcriptional control through unknown mechanisms is shown by thin arrows, other interaction and regulations are shown by dashed arrows. Transcriptional factor BMAL1:CLOCK regulates the expression of circadian clock proteins TIM, PERs RORs, REV-ERBα, and cell cycle-associated proteins WEE1 kinase and transcriptional factor c-Myc. TIM and PERs regulate cell cycle check-points through interaction with CHK1/ATR and CHK2/ATM complexes. RORs and REV-ERBα directly regulate the expression of cyclin-dependent kinase inhibitor p21. Several other cell cycle-associated proteins such as cyclins, cyclin-dependent kinases, and pro- and anti-apoptotic proteins are under circadian clock control, but the exact mechanism of regulation is unknown. The fate of the cell (proliferation or death) depends on the mutual balance of all these proteins. In turn cell proliferation and check-point proteins can regulate circadian clock function.

Table I. Post-translational modifications of BMAL1.

Modification	Enzyme	Modified residue	Effect	Reference
Phosphorylation	GSK3β	Ser17, Thr21	Increased ubiquitination degradation	(60)
	CK Iδ	ND	Increased transcriptional activity	(59)
	CK Iε	ND	Increased transcriptional activity	(59)
	MAPK	Ser527, Thr534, Ser599	Reduced transcriptional activity	(61)
	PKCα	ND	Regulation of circadian oscillation	(63)
Acetylation	CLOCK	LYS537	Increased transcriptional activity	(56)
Deacetylation	SIRT1	LYS537	Regulation of circadian oscillation	(77,90,91)
Sumoylation		LYS259	Increased transcriptional activity and degradation	(57,58)
Ubiquitination		LYS259	Increased degradation	(58)

Figure 3. Cell cycle control links the circadian clock with aging and carcinogenesis. Circadian clock, through transcriptional control and protein–protein interaction, regulates cellular metabolism, proliferation, ROS homeostasis, and DNA repair. Disruption of circadian clock function or deficiency of circadian clock proteins will interfere with the activity of these systems, which are known as critical regulators of aging and carcinogenesis.

Table II. Incidence of cancer risk as a result of shift-work.

Cancer Type	Incidence	Location	Reference
Breast cancer	Increased risk	Denmark	(80)
	Increased risk	US	(78,79)
	Increased risk	Iceland	(81,82)
	Decreased risk	China	(88)
Prostate cancer	Increased risk	Iceland, Nordic Countries, US, the Netherlands, Japan	(81,83–87)
Endometrial cancer	Increased risk	US	(92)^a
Colorectal cancer	Increased risk	US	(93)

^aIncrease only occurred in obese women.

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