**4. Roles of circadian clocks in regulation of cell cycle**

Circadian clock proteins appear to play roles in cell cycle control, acting as tumor suppressors. They control the timing of cell proliferation by transcriptional control of key cell cycle genes such as *Wee1*, *c-Myc*, and cyclin-dependent kinase inhibitor 1d (20 kDa protein, *p20*) [27–29]. In mammals, PER proteins directly interact with ATM and Chk2 proteins, inducing cell growth inhibition, cell cycle arrest, and apoptosis [17]. In addition, it has been also reported that PER1 and PER2 interact with the androgen receptor (AR) or estrogen receptor (ER), respectively, in that PER1 inhibits AR-dependent transcription and PER2 induces ER degradation [19, 30]. These findings support the idea that clock proteins act as key players in the cell cycle by interacting directly with and regulating the functions of the cell cycle regulators.

In zebrafish, the cell cycle is directly regulated by light [31, 32]. Light determines the timing of mitosis (M phase) and DNA synthesis (S phase), establishing a circadian rhythm for cell cycle progression. At the molecular level, cellular clocks establish the circadian expression of the cell cycle genes, zebrafish *Wee1* and *p20* [29, 32]. The Wee-l kinase controls the timing of the G2/M transition by directly phosphorylating and inhibiting cell division cycle2 (Cdc2)/cyclin B, leading to the suppression of mitotic cell division. In contrast, p20 regulates the G1/S transition of the cell cycle. Thus, the circadian control of these cell cycle regulators could be a mechanism establishing the circadian rhythm of cell cycle. Both cell cycle and circadian clock are endogenous pacemakers, and these mechanisms coexist in most eukaryotic cells and share several conceptual characteristics. The abovementioned findings point to functional links between the cell cycle and circadian clock in different organisms.

**17**

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

**5. Posttranslational modifications contributing to both the circadian** 

Posttranslational modifications of proteins regulate various biological processes at molecular levels, including gene expression, chromatin remodeling, and protein stabilization. These molecular events have essential roles in appropriately regulating biological phenomena, including development and circadian clock, by maintaining cellular functions, such as proliferation and molecular clocks, respectively. Posttranslational modifications, such as phosphorylation, sumoylation, and acetylation, control the transcriptional activity, subcellular localization, and stability of circadian clock regulators in multiple ways [4, 33]. In particular, the defects in phosphorylating the circadian clock regulators have been implicated in human sleep disorders [34, 35]. It is also well established that posttranslational modifications are vital for the regulation of the cell cycle and DDR. SIRT1 and casein kinase2 (CK2), already identified as responsible factors for posttranslational modifications of clock proteins [18, 36–39], have also been implicated in posttranslational modifications of proteins such as p53, forkhead box class O (FoxO), and E-cadherin that are involved in cellular metabolism, the cell cycle, and DDR [40, 41]. These findings support the hypothesis that the circadian clocks may be linked to other cellular processes, such as cell cycle control and DDR, through shared posttranslational modifications.

**6. Studies on light-dependent regulation of zebrafish circadian clock have revealed links of circadian clock with DNA repair and** 

To guarantee that an organism's behavior remains tied to the rhythms of its environment, the circadian clocks must respond to environmental stimuli to be reset [2, 10]. The main cue for animals is light, which is provided by the day-night cycle. The mammalian route for circadian entrainment by light uses the retinohypothalamic tract, which connects directly to the central clock located in the suprachiasmatic nucleus of the brain [42]. This makes it difficult to analyze the light entrainment mechanisms of the circadian clocks, especially at cellular levels. Zebrafish peripheral cellular clocks display a striking feature as they are directly light responsive [43]. Notably, in the zebrafish-cultured cell lines, oscillations of clock gene expression can be entrained to new light-dark cycle, and expression of clock genes, such as zebrafish *Cryptochrome1a* (*zCry1a*) and *Period2* (*zPer2*), is transactivated by an acute light pulse [44–46]. These observations show that zebrafish cultured cells have the clock components required for a light-induced reset of circadian clock, therefore, providing a valuable tool for the study of general light-dependent regulation of cellular clocks. Studies using zebrafish-cultured cells have contributed to identification of cellular signaling cascades involved in the light-dependent regulation of cellular clocks [47]. In several organisms, external stimuli are connected to a cell's nucleus via MAPK signaling pathways, such as p38 and extracellular signal-regulated kinase (ERK) [48]. Light has been reported to activate these signaling cascades in zebrafish cells (**Figure 2**) [49]. By a pharmacological approach, it has also been reported that the light-induced ERK activation triggers expression of *zPer2* and *zCry1a* genes, whereas the light-induced p38 activation suppresses it, highlighting a MAPKmediated cross-regulatory mechanism of the expression of circadian clock genes [49, 50]. Importantly, an increased understanding of the light-dependent cellular clock regulation in zebrafish has suggested intriguing associations of the circadian

clock with DNA repair and cellular DDR as described below.

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

**cellular DDR**

**clock regulation and the cellular DDR**

*A Molecular Link between the Circadian Clock, DNA Damage Responses, and Oncogene… DOI: http://dx.doi.org/10.5772/intechopen.81063*
