title: A molecular mechanism for circadian clock negative feedback.
abstract: 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.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hao A
authors.initials: HA
authors.lastname: Duong
authors.forename: Maria S
authors.initials: MS
authors.lastname: Robles
authors.forename: Darko
authors.initials: D
authors.lastname: Knutti
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Weitz
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks; D002940:Circadian Rhythm; D056931:Cryptochromes / Q000378:metabolism; D025461:Feedback, Physiological; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D000072670:PTB-Associated Splicing Factor; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D006657:Histones; D000072670:PTB-Associated Splicing Factor; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D056926:CLOCK Proteins; C538944:Clock protein, mouse; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D056264:Sin3 Histone Deacetylase and Corepressor Complex