Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop ...produces cycles of nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD(+)-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD(+) supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD(+) bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding.
The zebrafish represents a fascinating model for studying key aspects of the vertebrate circadian timing system. Easy access to early embryonic development has made this species ideal for ...investigating how the clock is first established during embryogenesis. In particular, the molecular basis for the functional development of the zebrafish pineal gland has received much attention. In addition to this dedicated clock and photoreceptor organ, and unlike the situation in mammals, the clocks in zebrafish peripheral tissues and even cell lines are entrainable by direct exposure to light thus providing unique insight into the function and evolution of the light input pathway. Finally, the small size, low maintenance costs and high fecundity of this fish together with the availability of genetic tools make this an attractive model for forward genetic analysis of the circadian clock. Here, we review the work that has established the zebrafish as a valuable clock model organism and highlight the key questions that will shape the future direction of research.
The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep‐to‐wake ...transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and CLOCK on clock‐controlled output genes, which results in tissue‐specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging.
Circadian clocks are evolutionarily conserved timekeepers that adapt cell physiology to diurnal cycles. This review discusses functions of circadian rhythms in stem cells and differentiated tissues, and how clocks influence stem cell maintenance, organ physiology, regeneration, and aging.
Clocks, cancer, and chronochemotherapy Sancar, Aziz; Van Gelder, Russell N
Science (American Association for the Advancement of Science),
01/2021, Letnik:
371, Številka:
6524
Journal Article
Recenzirano
The circadian clock coordinates daily rhythmicity of biochemical, physiologic, and behavioral functions in humans. Gene expression, cell division, and DNA repair are modulated by the clock, which ...gives rise to the hypothesis that clock dysfunction may predispose individuals to cancer. Although the results of many epidemiologic and animal studies are consistent with there being a role for the clock in the genesis and progression of tumors, available data are insufficient to conclude that clock disruption is generally carcinogenic. Similarly, studies have suggested a circadian time-dependent efficacy of chemotherapy, but clinical trials of chronochemotherapy have not demonstrated improved outcomes compared with conventional regimens. Future hypothesis-driven and discovery-oriented research should focus on specific interactions between clock components and carcinogenic mechanisms to realize the full clinical potential of the relationship between clocks and cancer.
The circadian transcriptional network is based on a competition between transcriptional activator and repressor complexes regulating the rhythmic expression of clock-controlled genes. We show here ...that the MYC-associated factor X, MAX, plays a repressive role in this network and operates through a MYC-independent binding to E-box-containing regulatory regions within the promoters of circadian BMAL1 targets. We further show that this "clock" function of MAX is required for maintaining a proper circadian rhythm and that MAX and BMAL1 contribute to two temporally alternating transcriptional complexes on clock-regulated promoters. We also identified MAX network transcriptional repressor, MNT, as a fundamental partner of MAX-mediated circadian regulation. Collectively, our data indicate that MAX regulates clock gene expression and contributes to keeping the balance between positive and negative elements of the molecular clock machinery.
To accommodate daily recurring environmental changes, animals show cyclic variations in behaviour and physiology, which include prominent behavioural states such as sleep-wake cycles but also a host ...of less conspicuous oscillations in neurological, metabolic, endocrine, cardiovascular and immune functions. Circadian rhythmicity is created endogenously by genetically encoded molecular clocks, whose components cooperate to generate cyclic changes in their own abundance and activity, with a periodicity of about a day. Throughout the body, such molecular clocks convey temporal control to the function of organs and tissues by regulating pertinent downstream programmes. Synchrony between the different circadian oscillators and resonance with the solar day is largely enabled by a neural pacemaker, which is directly responsive to certain environmental cues and able to transmit internal time-of-day representations to the entire body. In this Review, we discuss aspects of the circadian clock in Drosophila melanogaster and mammals, including the components of these molecular oscillators, the function and mechanisms of action of central and peripheral clocks, their synchronization and their relevance to human health.
Circadian rhythms regulate a remarkable variety of physiologic functions in living organisms. Circadian disruption is associated with tumorigenesis and tumor progression through effects on cancer ...cell biological properties, including proliferation, DNA repair, apoptosis, metabolism, and stemness. Emerging evidence indicates that circadian clocks also play an influential role in the tumor microenvironment (TME). This review outlines recent discoveries on how cancer cell clock components (including circadian clock and clock genes/proteins) regulate TME biology and, reciprocally, how TME clock components affect tumor growth, metastasis, and therapeutic response. An improved understanding of how clock components regulate the symbiosis between cancer cells and the TME will inform the development of novel clock-oriented therapeutic strategies, including immunotherapy.
Circadian clocks contribute to tumor growth and metastasis by regulating the biology of cancer cells and the tumor microenvironment (TME), as well as their symbiotic interactions.Cancer cell clock components affect TME biology via regulation of angiogenesis, tumor-promoting inflammation, and immune escape.TME clock components affect tumor progression via regulating cancer cell biological properties directly and by affecting the protumor TME indirectly.Characterizing clock component-regulated cancer cell–TME symbiosis might reveal unique therapeutic strategies, and targeting this symbiosis could increase the efficiency of immunotherapy.
Circadian rhythmicity is maintained by a set of core clock proteins including the transcriptional activators CLOCK and BMAL1, and the repressors PER (PER1, PER2, and PER3), CRY (CRY1 and CRY2), and ...CK1δ. In mice, peak expression of the repressors in the early morning reduces CLOCK- and BMAL1-mediated transcription/translation of the repressors themselves. By late afternoon the repressors are largely depleted by degradation, and thereby their expression is reactivated in a cycle repeated every 24 h. Studies have characterized a variety of possible protein interactions and complexes associated with the function of this transcription–translation feedback loop. Our prior investigation suggested there were two circadian complexes responsible for rhythmicity, one containing CLOCK–BMAL and the other containing PER2, CRY1, and CK1δ. In this investigation, we acquired data from glycerol gradient centrifugation and gel filtration chromatography of mouse liver extracts obtained at different circadian times to further characterize circadian complexes. In addition, anti-PER2 and anti-CRY1 immunoprecipitates obtained from the same extracts were analyzed by liquid chromatography–tandem mass spectrometry to identify components of circadian complexes. Our results confirm the presence of discrete CLOCK–BMAL1 and PER–CRY–CK1δ complexes at the different circadian time points, provide masses of 255 and 707 kDa, respectively, for these complexes, and indicate that these complexes are composed principally of the core circadian proteins.
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