A Common Origin: Signaling Similarities in the Regulation of the Circadian Clock and DNA Damage Responses

Circadian clocks are intrinsic, time-tracking systems that endow organisms with a survival advantage. Studies of animal models and human tumor samples have revealed that the disruption of circadian rhythms is an important endogenous factor that can contribute to mammalian cancer development. The core of the circadian clock mechanism is a cell-autonomous and self-sustained oscillator system mediated by a transcription/translation-based negative feedback loop that relies on positive and negative elements. Recent studies have implicated these core circadian components in the regulation of both the cell cycle and DNA damage responses (DDR). Indeed, the circadian feedback loop controls the timing of cell proliferation by regulating the expression of key cell cycle genes. Conversely, several intracellular signaling cascades and post-translational modifications that play important roles in the cell cycle and DDR are also essential for circadian clock regulation. Importantly, alteration of a cell's reduction oxidation (redox) state triggers the transduction of photic signals that regulate circadian clock gene transcription, suggesting that cellular responses to photo-oxidative stress may have been the evolutionary origin of the circadian clock. This review describes selected regulatory aspects of circadian machinery that are evidence of a molecular link between the circadian clock and DDR, focusing particularly on the signaling cascades involved in the light entrainment of the zebrafish circadian clock.