title: Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism.
abstract: Circadian rhythms in mammals are generated by a transcriptional negative feedback loop that is driven primarily by oscillations of PER and CRY, which inhibit their own transcriptional activators, CLOCK and BMAL1. Current models posit that CRY is the dominant repressor, while PER may play an accessory role. In this study, however, constitutive expression of PER, and not CRY1, severely disrupted the clock in fibroblasts and liver. Furthermore, constitutive expression of PER2 in the brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. These results demonstrate that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and in the intact organism. Our biochemical evidence supports an elegant mechanism for the disparity: PER2 directly and rhythmically binds to CLOCK:BMAL1, while CRY only interacts indirectly; PER2 bridges CRY and CLOCK:BMAL1 to drive the circadian negative feedback loop.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Rongmin
authors.initials: R
authors.lastname: Chen
authors.forename: Aaron
authors.initials: A
authors.lastname: Schirmer
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Lee
authors.forename: Hyeongmin
authors.initials: H
authors.lastname: Lee
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.forename: Choogon
authors.initials: C
authors.lastname: Lee
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases; D056926:CLOCK Proteins; C538944:Clock protein, mouse