Abstract
The circadian clock allows physiological systems to adapt to their changing environment by synchronizing their timings in response to external stimuli. Previously, we reported clock-controlled adaptive responses to heat-shock and oxidative stress and showed how the circadian clock interacts with BMAL1 and HSF1. Here, we present a similar clock-controlled adaptation to UV damage. In response to UV irradiation, HSF1 and tumor suppressor p53 regulate the expression of the clock gene Per2 in a time-dependent manner. UV irradiation first activates the HSF1 pathway, which subsequently activates the p53 pathway. Importantly, BMAL1 regulates both HSF1 and p53 through the BMAL1–HSF1 interaction to synchronize the cellular clock. Based on these findings and transcriptome analysis, we propose that the circadian clock protects cells against the UV stress through sequential and hierarchical interactions between the circadian clock, the heat shock response, and a tumor suppressive mechanism.
Highlights
The circadian clock allows physiological systems to adapt to their changing environment by synchronizing their timings in response to external stimuli
We evaluated the optimal dose of UV irradiation that synchronizes the circadian clock to create a model for the genotoxic stress response of the mammalian cellular clock
We performed a ChIP assay at 2 h after stimulation to assess the acute heat-shock factor-1 (HSF1) response to the UV irradiation and found that HSF1 bound dominantly to HSE2 but not to HSE1, as observed with heat-shock-treated cells. These results demonstrated that UV irradiation triggers activation of heat-shock response (HSR), inducing HSF1 binding to the HSE2 site on the Per[2] promoter, thereby enhancing Per[2] expression
Summary
The circadian clock allows physiological systems to adapt to their changing environment by synchronizing their timings in response to external stimuli. In response to UV irradiation, HSF1 and tumor suppressor p53 regulate the expression of the clock gene Per[2] in a time-dependent manner. BMAL1 regulates both HSF1 and p53 through the BMAL1–HSF1 interaction to synchronize the cellular clock. Based on these findings and transcriptome analysis, we propose that the circadian clock protects cells against the UV stress through sequential and hierarchical interactions between the circadian clock, the heat shock response, and a tumor suppressive mechanism. The synchronized clock, in turn, regulates the expression of stress resistance genes via activation of the HSR pathway and various adaptive protection pathways that control antioxidant and cell survival responses to protect cells from the stressors[5,6,7]. We analyzed the interplay between the clock, HSR and tumor suppressor system and found that these components directly interacted with each other and trans-activation of the stress response factors mutually affected their functions
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