Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism.
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.
Chen
Rongmin
R
Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
Schirmer
Aaron
A
Lee
Yongjin
Y
Lee
Hyeongmin
H
Kumar
Vivek
V
Yoo
Seung-Hee
SH
Takahashi
Joseph S
JS
Lee
Choogon
C
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
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