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

Abstract

INTRODUCTIONFrom bacteria to humans, almost all organisms can adapt the timing of their physiology to the cyclic changes of their environment, thanks to a naturally-selected intrinsic timekeeping system called the circadian clock. 1) The circadian clock enhances the physiological efficiency and survival of an organism by organizing its behavior and body functions. 2,3) During the circadian day, the organism's physiology is given over to catabolic processes, whereas the anabolic functions of growth, repair and consolidation occur at night. To achieve this schedule in mammals, the circadian clock regulates a number of physiological functions, including sleep and wakefulness, food intake, body temperature, cardiovascular and renal activity, hormone production, hepatic metabolism and immune responses. 4,5) Accordingly, disruption of the circadian clock in humans has been linked to profound effects on health, including insomnia, stomach ailments, depression and cancer. 4,5) In most organisms, the molecular mechanisms underlying the establishment and maintenance of biological rhythms comprise interconnected transcription-translation feedback loops in which some clock factors repress their own transcription once they have attained critical levels. 2,3) These oscillators have the property of being endogenous and cellautonomous systems that maintain their rhythm in the absence of external time cues. 6) Both vertebrates and invertebrates have circadian oscillators scattered throughout their bodies. 7,8) In mammals, the circadian system is composed of both central and peripheral oscillators. 7) The mammalian central clock is located in the suprachiasmatic nucleus (SCN) within the anterior hypothalamus of the brain. 9) This central clock acts as a coordinator and provides time signals via both neural and humoral routes that entrain independent peripheral clocks. Dysfunction of the central clock does not inactivate the peripheral clocks but instead causes individual peripheral oscillators to become temporally uncoupled. [10][11][12] To guarantee that an organism's behavior remains tied to the rhythms of its environment, the circadian clock must be able to reset itself in response to environmental cues. 9,13,14) The main environmental stimulus for organisms is light, which is provided in day-night cycles. Mammals have no photoreceptors in peripheral tissues, 15) so that the effect of light on peripheral clocks is indirect. 13) For the mammalian clock, the SCN integrates photic cues from the retina and uses neural and humoral signals to transmit this information to peripheral clocks, synchronizing them. [16][17][18] This communication between the central and peripheral clocks results in the seamless regulation of fundamental physiological functions. 4,8) Interestingly, peripheral clocks can also respond directly to SCN-independent signals such as feeding and temperature change. 19,20) However, the physiological role of SCN-independent responses of peripheral clocks is not yet fully understood. A recent study has reported that ...

Diphenyleneiodonium Chloride, an Inhibitor of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase, Suppresses Light-Dependent Induction of Clock and DNA Repair Genes in Zebrafish

“…Once the PER and CRY proteins have been translated, they form heterodimers that can then translocate to the nucleus to repress CLOCK (NPAS2) : BMAL-mediated transcription through direct protein-protein interaction. These interactions then set up the rhythmic oscillations of gene expression that drive the circadian clock.Zebrafish have been established as an attractive vertebrate model suitable for the examination of the light signaling pathway and its impact on the circadian clock.5) Not only are the molecular components of the mammalian and zebrafish circadian oscillators highly similar, 5,6) but zebrafish clocks have the unusual attribute of being directly light-responsive. …”

“…6,12) Importantly, studies in zebrafish have revealed critical roles for the cellular redox state and mitogen activated protein kinase (MAPK) signaling pathways in the regulation of light-dependent gene expression. 5,10,13) In a variety of organisms, light induces ROS production that alters the reduction-oxidation (redox) state within cells. In zebrafish cells, a light-induced change in redox state stimulates intracellular extracellular signal-regulated kinase (ERK)/MAPK signaling that transduces photic signals.…”

Fototransdução em células embrionárias ZEM-2S do peixe teleósteo Danio rerio

“…Essa é uma questão ainda muita debatida no meio científico, no qual vários candidatos são propostos para desempenhar o papel do fotopigmento circadiano em relógios periféricos de zebrafish. Dentre eles podemos destacar: (i) opsinas como teleost multiple tissue opsin (tmt-opsin) e a vertebrate ancient opsin (va-opsin); (ii) os criptocromos que, em drosófilas, são responsáveis pela fotorrecepção circadiana ; (iii) processos de estresse oxidativo através da ativação de oxidases contendo flavinas e produção de espécies reativas de oxigênio (ROS) (Uchida et al, 2010).…”

“…A possível interação entre a via dos fosfoinositídeos e a via de AMPc/PKA foi avaliada em melanóforos de X. leavis (Isoldi et al, 2010 (Golombeck & Ralph, 1994;Golombeck & Ralph, 1995;Ding et al, 1994;Wanabe et al, 1995;Fukushima et al, 1997;Melo et al, 1997;Ferreyra et al, 1998;Agostino et al, 2004 (Gonzalez & Montminy, 1989), CaMK (Sheng et al, 1991) e MAPK (Xing et al, 1996). Os argumentos a favor da integração das vias de NO e MAPK vêm de estudos provando que a integridade dessas duas vias é essencial na fosforilação de CREB nos NSQs (Ding et al, 1994;Ding et al, 1997;Obrietan et al, 1999), e da demonstração de que a produção de NO é fundamental para a atividade de fosforilação das ERK em culturas primárias de córtex neural (Yun et al, 1998 (Hirayama et al, 2007;Uchida et al, 2010). Através desse sistema, o fóton absorvido por essas enzimas levaria à produção de espécies reativas de oxigênio (ROS), ativação da via das MAPKs e regulação dos genes de relógio, porém a participação efetiva dessas oxidases na fotorrecepção ainda não foi comprovada.…”

“…Na realidade, esse dois mecanismos aparentemente convergem para uma mesma via de sinalização, nesse caso, a via das MAPKs (Cermakian et al, 2003;Hirayama et al, 2007). A diferença entre esses dois mecanismos pode residir nas moléculas que ativam a via das MAPKs: no estresse oxidativo a ativação é feita através de ROS (Hirayama et al, 2007;Uchida et al, 2010), enquanto que na via de sinalização proposta neste trabalho a ativação se daria através de espécies reativas de nitrogênio (RNS). Um grande número de trabalhos vem demonstrando que as RNS, assim como as ROS, podem atuar nas cascatas de sinalização através de modificações pós-transcricionais, fornecendo um controle da conformação espacial e temporal de proteínas, o que resultaria em um ajuste fino da sua atividade (para revisão ler Hess et al, 2005;Martinez-Ruiz et al, 2011).…”