International Journal of Molecular Zoology 2024, Vol.14, No.3, 166-181 http://animalscipublisher.com/index.php/ijmz 167 2 Molecular Mechanisms of Circadian Rhythms 2.1 Core components of the molecular clock The molecular clock in animals is primarily driven by a set of core clock genes that form a transcription-translation feedback loop (TTFL). In mammals, the basic helix-loop-helix (bHLH) PAS (PER-ARNT-SIM) transcription factors CLOCK and BMAL1 are central to this mechanism. These proteins form a heterodimer that activates the transcription of Period (Per) and Cryptochrome (Cry) genes. The protein products of these genes then inhibit the activity of the CLOCK:BMAL1 complex, thereby closing the feedback loop and generating rhythmic oscillations with a period of approximately 24 hours (King and Takahashi, 2000; Lowrey and Takahashi, 2000; Partch et al., 2014; Takahashi, 2015). In addition to the core loop, there are auxiliary loops that help stabilize and fine-tune the circadian rhythms. For instance, the nuclear receptors REV-ERBα and RORα form a secondary feedback loop that regulates the expression of Bmal1, adding another layer of control to the circadian system (Isojima et al., 2003; Schmutz et al., 2010). This intricate network of feedback loops ensures the robustness and precision of the circadian clock. 2.2 Genetic regulation of circadian rhythms The genetic regulation of circadian rhythms involves not only the core clock genes but also a multitude of other genes that interact with the core components. For example, the light-dark cycle, a primary environmental cue, influences the expression of clock genes through photic entrainment pathways. In mammals, light signals received by the retina are transmitted to the suprachiasmatic nucleus (SCN) in the hypothalamus, which acts as the master circadian pacemaker. This signal ultimately leads to the resetting of the core clock mechanism in the SCN by modulating the expression of Per and Cry genes (Lowrey and Takahashi, 2000; Meyer-Bernstein and Sehgal, 2001). Moreover, post-translational modifications such as phosphorylation, nuclear entry, and degradation of clock proteins are crucial for the proper functioning of the circadian clock. These modifications ensure that the feedback loops operate with the necessary precision and stability. For instance, the phosphorylation of PER proteins by casein kinase 1 (CK1) regulates their stability and nuclear translocation, which is essential for the timely repression of CLOCK:BMAL1 activity (Isojima et al., 2003). 2.3 Feedback loops and their role in maintaining circadian rhythms Feedback loops are fundamental to the maintenance of circadian rhythms. The primary TTFL involves the activation of Per and Cry genes by the CLOCK:BMAL1 complex, followed by the inhibition of this complex by the PER and CRY proteins. This loop generates the basic oscillatory pattern of the circadian clock (King and Takahashi, 2000; Lowrey and Takahashi, 2000; Takahashi, 2015). In addition to the primary loop, secondary feedback loops involving nuclear receptors such as REV-ERBα and RORα play a critical role in stabilizing the circadian rhythms. These receptors regulate the expression of Bmal1, thereby influencing the activity of the CLOCK:BMAL1 complex. The interaction between these loops ensures that the circadian clock can adapt to changes in environmental conditions while maintaining its intrinsic rhythmicity (Figure 1) (Isojima et al., 2003; Schmutz et al., 2010). Furthermore, recent studies have highlighted the importance of non-transcriptional mechanisms in circadian timekeeping. For example, the oxidation of peroxiredoxin proteins has been identified as a transcription-independent rhythmic biomarker, suggesting that post-translational mechanisms also contribute significantly to the maintenance of circadian rhythms (O’Neill et al., 2010). This indicates that the oldest oscillator components may be non-transcriptional in nature and conserved across different kingdoms of life. The molecular mechanisms of circadian rhythms in animals involve a complex interplay of transcriptional and post-transcriptional processes. The core components of the molecular clock, genetic regulation, and multiple feedback loops work together to generate and maintain the precise 24-hour cycles that are essential for the temporal organization of biological functions.
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