Circadian oscillation of nucleotide excision repair in mammalian brain

Abstract

The circadian clock regulates the daily rhythms in the physiology and behavior of many organisms, including mice and humans. These cyclical changes at molecular and macroscopic levels affect the organism's response to environmental stimuli such as light and food intake and the toxicity and efficacy of chemo-and radiotherapeutic agents. In this work, we investigated the circadian behavior of the nucleotide excision repair capacity in the mouse cerebrum to gain some insight into the optimal circadian time for favorable therapeutic response with minimal side effects in cancer treatment with chemotherapeutic drugs that produce bulky adducts in DNA. We find that nucleotide excision repair activity in the mouse cortex is highest in the afternoon/evening hours and is at its lowest in the night/early morning hours. The circadian oscillation of the repair capacity is caused at least in part by the circadian oscillation of the xeroderma pigmentosum A DNA damage recognition protein.cancer treatment ͉ chronotherapy ͉ circadian clock ͉ xeroderma pigmentosum A C ircadian rhythm is the daily oscillation in the biochemical, behavioral, and physiological functions of organisms (1, 2). Circadian clock disruption by environmental factors and behavioral patterns has been implicated as a contributing factor in carcinogenesis (2-4). Similarly, a limited number of studies have indicated that the efficacy of chemo-and radiotherapy of cancer and the side effects of these treatments are markedly influenced by the circadian time of administration of these agents (4, 5). Although attempts have been made to put these findings to practice in preventive and clinical medicine, the empirical nature of the observations and the lack of mechanistic explanations for the findings have been serious obstacles to making use of these findings in cancer prevention and treatment.Important progress in the past decade has provided a reasonably detailed model for the mammalian circadian clock. In mice and humans, the clock is present in essentially every cell and is generated by an autoregulatory transcription-translation feedback loop (TTFL) (1, 2): Clock and Bmal1 transcription factors bind to the E-box promoter elements of the Cryptochrome (Cry)1 and 2 and Period (Per)1 and 2 genes and activate their transcription. The Cry and Per proteins make oligomeric complexes that, after a time delay, inhibit the Clock⅐Bmal1 complex and hence the transcription of the Cry and Per genes. The time delay between the synthesis of Cry and Per and their action as repressors generates an oscillatory pattern of expression of Crys and Pers and other clock controlled genes that are regulated by Clock⅐Bmal1 but are not part of the TTFL. It is this oscillation of gene expression that affects cellular and organismic function to give rise to the circadian rhythm at a macroscopic level. These peripheral circadian oscillations are synchronized with one another by the master circadian clock that is located above the optic chiasma, in the suprachiasmatic nuclei (SCN). The SCN coordina...

Control of skin cancer by the circadian rhythm

“…Previously, we reported that the transcription of the xpa gene and the level of XPA protein exhibited circadian rhythmicity in some mouse tissues such as the brain and the liver but not in others such as testis (11,12). This rhythmicity or the lack thereof (in clock mutant mice) was associated with an oscillatory or a constant rate of repair activity as a function of time of day, respectively.…”

“…The dual incision is carried out by six excision repair factors: RPA, xeroderma pigmentosum group A (XPA), XPC, TFIIH, XPG, and XPF-ERCC1 (10). Recently, in a study that analyzed liver and brain tissues from mice, it was found that XPA, a critical protein involved in damage recognition and a rate-limiting factor in excision repair, is controlled by the core molecular circadian clock (11,12). As a consequence, excision repair activity exhibited circadian rhythmicity in these organs, increasing during the day to reach a maximum at 4-6:00 PM and decreasing during the night to a minimum at 4-6:00 AM.…”

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle

“…Of the many processes being regulated by the circadian clock, some of the most profound are those related to specific cell-cycle events, DNA repair, and apoptosis (2,4,5,(21)(22)(23)(24)(25). The dynamics of the coupling we describe here are likely to be controlled through multiple and interacting pathways.…”

The daily rhythm of mice

“…The above results illustrate the dichotomy in biological consequences of the disruption of the circadian clock with respect to cancer development. There are probably complex interconnections between carcinogenesis, ageing and the individual components of the circadian clock because nucleotide excision repair has been suggested to be under clock influence [65,66] and DNA damage affects phase resetting in the murine circadian clock [67].…”