title: Stoichiometric relationship among clock proteins determines robustness of circadian rhythms.
abstract: The mammalian circadian oscillator is primarily driven by an essential negative feedback loop comprising a positive component, the CLOCK-BMAL1 complex, and a negative component, the PER-CRY complex. Numerous studies suggest that feedback inhibition of CLOCK-BMAL1 is mediated by time-dependent physical interaction with its direct target gene products PER and CRY, suggesting that the ratio between the negative and positive complexes must be important for the molecular oscillator and rhythm generation. We explored this idea by altering expression of clock components in fibroblasts derived from Per2(Luc) and Per mutant mice, a cell system extensively used to study in vivo clock mechanisms. Our data demonstrate that the stoichiometric relationship between clock components is critical for the robustness of circadian rhythms and provide insights into the mechanistic organization of the negative feedback loop. Our findings may explain why certain mutant mice or cells are arrhythmic, whereas others are rhythmic, and suggest that robustness of circadian rhythms can be increased even in wild-type cells by modulating the stoichiometry.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32312, USA.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Lee
authors.forename: Rongmin
authors.initials: R
authors.lastname: Chen
authors.forename: Hyeong-min
authors.initials: HM
authors.lastname: Lee
authors.forename: Choogon
authors.initials: C
authors.lastname: Lee
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D002940:Circadian Rhythm / Q000502:physiology*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D056925:Circadian Rhythm Signaling Peptides and Proteins; C538964:Cry1 protein, mouse; D056931:Cryptochromes; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D056926:CLOCK Proteins; C538944:Clock protein, mouse