A molecular mechanism for circadian clock negative feedback.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE

Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-

Circadian Clocks* ; Circadian Rhythm* ; Feedback, Physiological*; Period Circadian Proteins/*genetics ; RNA-Binding Proteins/*metabolism ; Repressor Proteins/*metabolism; ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Animals ; CLOCK Proteins/genetics ; CLOCK Proteins/metabolism ; Cryptochromes/metabolism ; Histone Deacetylase 1/metabolism ; Histones/metabolism ; Liver/metabolism ; Lung/metabolism ; Mass Spectrometry ; Mice ; PTB-Associated Splicing Factor ; Period Circadian Proteins/metabolism ; Promoter Regions, Genetic ; RNA-Binding Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Sin3 Histone Deacetylase and Corepressor Complex ; Transcription, Genetic

Circadian rhythms in mammals are generated by a feedback loop in which the three PERIOD (PER) proteins, acting in a large complex, inhibit the transcriptional activity of the CLOCK-BMAL1 dimer, which represses their own expression. Although fundamental, the mechanism of negative feedback in the mammalian clock, or any eukaryotic clock, is unknown. We analyzed protein constituents of PER complexes purified from mouse tissues and identified PSF (polypyrimidine tract-binding protein-associated splicing factor). Our analysis indicates that PSF within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and that the PER complex thereby rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription. These findings provide a function for the PER complex and a molecular mechanism for circadian clock negative feedback.

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T32 NS007484 United States NS NINDS NIH HHS

0 (ARNTL Transcription Factors)
0 (Bmal1 protein, mouse)
0 (Cry2 protein, mouse)
0 (Cryptochromes)
0 (Histones)
0 (PTB-Associated Splicing Factor)
0 (Per1 protein, mouse)
0 (Per2 protein, mouse)
0 (Period Circadian Proteins)
0 (RNA-Binding Proteins)
0 (Recombinant Fusion Proteins)
0 (Repressor Proteins)
0 (SIN3A transcription factor)
EC 2.3.1.48 (CLOCK Proteins)
EC 2.3.1.48 (Clock protein, mouse)
EC 3.5.1.98 (Hdac1 protein, mouse)
EC 3.5.1.98 (Histone Deacetylase 1)
EC 3.5.1.98 (Sin3 Histone Deacetylase and Corepressor Complex)

Date Created: 20110618 Date Completed: 20110628 Latest Revision: 20240519

20240519

PMC3859310

10.1126/science.1196766

21680841