Dataset Information

Molecular mechanism of the repressive phase of the mammalian circadian clock.

ABSTRACT: The mammalian circadian clock consists of a transcription-translation feedback loop (TTFL) composed of CLOCK-BMAL1 transcriptional activators and CRY-PER transcriptional repressors. Previous work showed that CRY inhibits CLOCK-BMAL1-activated transcription by a "blocking"-type mechanism and that CRY-PER inhibits CLOCK-BMAL1 by a "displacement"-type mechanism. While the mechanism of CRY-mediated repression was explained by both in vitro and in vivo experiments, the CRY-PER-mediated repression in vivo seemed in conflict with the in vitro data demonstrating PER removes CRY from the CLOCK-BMAL1-E-box complex. Here, we show that CRY-PER participates in the displacement-type repression by recruiting CK1δ to the nucleus and mediating an increased local concentration of CK1δ at CLOCK-BMAL1-bound promoters/enhancers and thus promoting the phosphorylation of CLOCK and dissociation of CLOCK-BMAL1 along with CRY from the E-box. Our findings bring clarity to the role of PER in the dynamic nature of the repressive phase of the TTFL.

SUBMITTER: Cao X

PROVIDER: S-EPMC7812753 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Molecular mechanism of the repressive phase of the mammalian circadian clock.

Cao Xuemei X Yang Yanyan Y Selby Christopher P CP Liu Zhenxing Z Sancar Aziz A

Proceedings of the National Academy of Sciences of the United States of America 20201221 2

The mammalian circadian clock consists of a transcription-translation feedback loop (TTFL) composed of CLOCK-BMAL1 transcriptional activators and CRY-PER transcriptional repressors. Previous work showed that CRY inhibits CLOCK-BMAL1-activated transcription by a "blocking"-type mechanism and that CRY-PER inhibits CLOCK-BMAL1 by a "displacement"-type mechanism. While the mechanism of CRY-mediated repression was explained by both in vitro and in vivo experiments, the CRY-PER-mediated repression in ...[more]

PMID: 33443219

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Project description:In mammals, most cells in the brain and peripheral tissues generate circadian (∼24 h) rhythms autonomously. These self-sustained rhythms are coordinated and entrained by a master circadian clock in the suprachiasmatic nucleus (SCN). Within the SCN, the individual rhythms of each neuron are synchronized through intercellular signaling. One important feature of SCN is that the synchronized period is close to the population mean of cells' intrinsic periods. In this way, the synchronized period of the SCN stays close to the periods of cells in peripheral tissues. This is important because the SCN must entrain cells throughout the body. However, the mechanism that drives the period of the coupled SCN cells to the population mean is not known. We use mathematical modeling and analysis to show that the mechanism of transcription repression in the intracellular feedback loop plays a pivotal role in regulating the coupled period. Specifically, we use phase response curve analysis to show that the coupled period within the SCN stays near the population mean if transcriptional repression occurs via protein sequestration. In contrast, the coupled period is far from the mean if repression occurs through highly nonlinear Hill-type regulation (e.g., oligomer- or phosphorylation-based repression), as widely assumed in previous mathematical models. Furthermore, we find that the timescale of intercellular coupling needs to be fast compared to that of intracellular feedback to maintain the mean period. These findings reveal the important relationship between the intracellular transcriptional feedback loop and intercellular coupling. This relationship explains why transcriptional repression appears to occur via protein sequestration in multicellular organisms, mammals, and Drosophila, in contrast with the phosphorylation-based repression in unicellular organisms and syncytia. That is, transition to protein sequestration is essential for synchronizing multiple cells with a period close to the population mean (∼24 h).

Dataset Information

Molecular mechanism of the repressive phase of the mammalian circadian clock.

Publications

Molecular mechanism of the repressive phase of the mammalian circadian clock.

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