2020
DOI: 10.1073/pnas.2021174118
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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 … Show more

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Cited by 112 publications
(117 citation statements)
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“…Although the basic mechanism of the mammalian clock is currently known, detailed mechanistic aspects at the molecular level, needed for possible medical intervention, are still being worked out. Figure 1 shows a model of the mammalian clock based on our recent work ( 22 , 23 , 24 , 25 ) that incorporates earlier work by many investigators in the field. Figure 1 B shows that the activating (CLOCK-BMAL1) and the repressive (CRY-PER-CK1δ) proteins are in two separate complexes.…”
mentioning
confidence: 99%
“…Although the basic mechanism of the mammalian clock is currently known, detailed mechanistic aspects at the molecular level, needed for possible medical intervention, are still being worked out. Figure 1 shows a model of the mammalian clock based on our recent work ( 22 , 23 , 24 , 25 ) that incorporates earlier work by many investigators in the field. Figure 1 B shows that the activating (CLOCK-BMAL1) and the repressive (CRY-PER-CK1δ) proteins are in two separate complexes.…”
mentioning
confidence: 99%
“…Whereas CRY1 inhibits BMAL1 transactivation via binding and blocking productive interactions with transcriptional coactivators, PER:CRY complexes permit an alternative mode of repression (8,34). We demonstrate that increasing PER:CRY leads to an overall reduction in the ability for CLOCK:BMAL1 to remain bound through direct dimerization and manipulation of DNA unbinding.…”
Section: Compromise Between E-box Visitations and Occupancy Via Per:cry Mediated Displacementmentioning
confidence: 84%
“…4I). In this sense, PER2 acts both as part of a transcriptional repressor complex and as a facilitator of CLOCK:BMAL1 mobility to bind new target sites (34).…”
Section: Mathematical Modelling Demonstrates Dual Function Of Per2:cry1 Mediated Repressionmentioning
confidence: 99%
See 1 more Smart Citation
“…Very similarly, PER1/2 are dependent upon CRY1/2 for their nuclear accumulation (10). Following their translation and accumulation in the nucleus, the PER and CRY heterodimer suppresses the transcriptional activity of BMAL1::CLOCK, likely by recruiting Casein Kinase 1 d (CKd), resulting in the phosphorylation of the transcriptional complex and dissociation from the E-box (11). This serves as a negative feedback loop in that PER::CRY suppress their own transcription.…”
Section: The Transcription Translation Feedback Loopmentioning
confidence: 99%