p53 regulates Period2 expression and the circadian clock

Abstract

The mechanistic interconnectivity between circadian regulation and the genotoxic stress response remains poorly understood. Here we show that the expression of Period 2 (Per2), a circadian regulator, is directly regulated by p53 binding to a response element in the Per2 promoter. This p53 response element is evolutionarily conserved and overlaps with the E-Box element critical for BMAL1/CLOCK binding and its transcriptional activation of Per2 expression. Our studies reveal that p53 blocks BMAL1/CLOCK binding to the Per2 promoter leading to repression of Per2 expression. In the suprachiasmatic nucleus (SCN), p53 expression and its binding to the Per2 promoter are under circadian control. Per2 expression in the SCN is altered by p53 deficiency or stabilization of p53 by Nutlin-3. Behaviorally, p53−/− mice have a shorter period length that lacks stability and they exhibit impaired photo-entrainment to a light pulse under a free-running state. Our studies demonstrate that p53 modulates mouse circadian behavior.

Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling

“…The best-fit mathematical model indeed included a non-zero circadian amplitude for the parameter k apop , which represents the DNA damage response phenotype, including the P53 network, DNA repair and, eventually, apoptosis. Besides its regulatory effect on apoptosis, P53 also regulates the molecular clock so that P53 mutation could modify the circadian rhythms of the protein activities involved in irinotecan chronopharmacology and therefore alter the circadian pattern in irinotecan cytotoxicity (29,34).…”

LINE-1 activity as molecular basis for genomic instability associated with light exposure at night

“…For example, LAN can disrupt DNA damage response and repair, metabolism, and other signaling networks. [47][48][49][50][51][52] L1 proteins have been reported to associate with numerous host proteins, 20,34 and multiple cellular factors are known to suppress L1 mobilization in cultured cells. These findings suggest that the balanced existence of these complex suppressive interactions could be upset by LAN (Fig.…”

The unfolded protein response, inflammation, oscillators, and disease: a systems biology approach

“…Tumor suppressor p53 is an antagonizer of the UPR [157], an oscillator itself [158,159], and a regulator of PER2 expression [160]. In p53-deficient mice, submitted to chronic ER stress by tunicamycin (an ER-resident glycosylase), there was a more pronounced UPR (i.e.…”

“…The mechanism involves the blocking by p53 of the binding of CLOCK/BMAL1 to the PER2 promoter, resulting in the repression of PER2 expression [160]. Not much is known about how such a direct effect of p53 on the circadian clock of the SCN interconnects with its own pulsating effect on peripheral tissues.…”