**1. Introduction**

Circadian (derived from Latin "around the day") clocks constitute ubiquitous processes that regulate various biochemical and physiological events occurring with a 24 h periodicity, even in the absence of external cues [1, 2]. Under natural conditions, clocks are entrained to a 24 h day by environmental time cues, most commonly light. Circadian clocks are established in cell-autonomous oscillators, referred to as cellular clocks, which are controlled by a transcription/translationbased negative feedback loop [3, 4]. In humans, the circadian clock generates circadian rhythms in synthesis and release of hormones and cardiovascular activities such as heart rate, blood pressure, and vascular tone [5, 6]. Moreover, immune responses show temporal changes in antibody levels and total number of lymphocytes, which are related to circadian variations [7]. Therefore, dysfunction of the clock can cause a variety of diseases. In particular, it has been reported that the circadian clocks are associated with tumor suppression in vivo, indicative of the theoretical foundations for cancer chronotherapy [8, 9].

At the molecular level, the circadian clocks can be divided into three conceptual components [10, 11]. The first is the pacemaker, dedicated to generating and sustaining circadian rhythms by receiving and integrating signals from external

time cues. The second component is the input which refers to the pathway through which these cues are perceived and act upon the central pacemaker. The third element applies to how the clock affects physiology, which is achieved through the output pathways. In vertebrates, the cellular clocks are comprised of the circadian locomotor output cycles kaput (CLOCK), neuronal PAS domain-containing protein 2 (NPAS2), brain and muscle arnt-like protein-1 (BMAL), period (PER), and cryptochrome (CRY) proteins (**Figure 1A**) [11]. CLOCK or NPAS2 heterodimerize with BMAL to form an active transcription complex that transactivates clock-controlled genes, including *Cry* and *Per*. Once the CRY and PER proteins have been translated, they are translocated to the nucleus, where they inhibit CLOCK(NPAS2):BMALmediated transcription through a direct protein-protein interaction. Importantly,

### **Figure 1.**

*Molecular mechanisms establishing circadian clocks in vertebrates. (A) Model of the vertebrate cellular clocks. Two basic helix-loop-helix PAS domain-containing transcription factors CLOCK and BMAL constitute the positive elements. When these transcription factors heterodimerize, they bind to E-boxes to drive the transcription of the negative components of the clock, Per and Cry genes. The products of these clock genes then negatively regulate their own expression, setting up the rhythmic oscillations of gene expression that drive the circadian clocks. CLOCK:BMAL complex also regulates clock-controlled genes, whose products mediate the "output" function of the clocks. CK1 phosphorylates PER protein, which is required for ubiquitination of PER and its subsequent degradation. An essential prerequisite for the circadian feedback loop is a short half-life of clock proteins. Thus, CK1-mediated degradation of PER is critical for maintenance of circadian rhythmicity of cellular clock. (B) Schematic representation of the proteins that are acetylated by CLOCK protein.*

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and tumorigenesis.

**components of DDR pathways**

*A Molecular Link between the Circadian Clock, DNA Damage Responses, and Oncogene…*

when active, the CLOCK (NPAS2):BMAL complex stimulates the transcription of many other clock-controlled genes. These genes in turn influence functions external to the oscillatory mechanism itself and mediate the "output" function of the clock. This accounts in part for the presence of circadian rhythms in a variety of

The phenotypes of mice with targeted disruptions of the genes encoding cellular clock's components have revealed direct links between the circadian clock and noncircadian aspects of animal physiology [6, 9]. In particular, these findings argue in favor of a major role played by the circadian machinery in cellular genotoxic stress responses and reveal intriguing links between the DNA damage responses (DDR) pathways and the circadian clocks. In this review, we summarize the evidence and

**2. The relationship between transcriptional regulation of oncogenes and** 

The disruption of circadian clocks can have a profound effect on animal health

The Wingless-related integration site (Wnt) signaling pathways collectively play important roles in developmental, proliferative, and cell death processes [13]. Mutations in genes encoding the various components of Wnt pathways have been identified that contribute to various types of cancer including hepatocellular carcinoma, pancreatic tumors, ovarian cancer, and breast cancer. Importantly, there are several lines of evidence that suggest the existence of an interaction between circadian clocks and Wnt signaling pathways. Previous study have performed microarray-based screening for circadian genes in several mouse tissues and have constructed a publicly accessible database, by which users can query for finding circadianly regulated genes or for the study of the temporal expression patterns of their genes of interest [14]. Interestingly, in this database, several Wnt signaling pathway genes, such as *Axin2*, *Frizzled3* (*Fzd3*), and *Disheveled* (*Dvl1*), show a circadian pattern of expression, suggesting the possibility that circadian clocks control transcription of Wnt signaling pathway genes. The future study of the connecting routes that link the circadian transcriptional machinery to Wnt signaling pathway will reveal a molecular link between circadian clock deficiency

**3. Possible roles of clock proteins in functional regulation of crucial** 

The activities associated with the physiological processes are organized in daily manner: during the daytime, the animal's physiology is given over to the catabolic processes, whereas at night, it concentrates on the anabolic functions of growth, repair, and consolidation [5, 6]. Disrupt, the time-dependent regulation of physiological functions in animals has profound effects on their health. In particular, many studies have provided evidence that disruption of the circadian clocks results

and is linked to abnormal development and cancer [6, 9]. Expression of the circadian clock genes has been reported to be dysregulated in human cancers [12]. The circadian transcriptional machinery, cellular clock, has been reported to control expression of tumor suppressors. Thus, the abnormal control of clock genes' expression in cancer cells activates oncogenic signaling pathways by functional inhibition of tumor suppressors, such as ataxia telangiectasia mutated

*DOI: http://dx.doi.org/10.5772/intechopen.81063*

explore the implications of such a link.

(ATM), p53, p21, and WEE1 [12].

physiological processes.

**circadian clocks**
