Rhythmic PER Abundance Defines a Critical Nodal Point for Negative Feedback within the Circadian Clock Mechanism

Rongmin Chen, Aaron Schirmer, Yongjin Lee, Hyeongmin Lee, Vivek Kumar, Seung Hee Yoo, Joseph S. Takahashi, Choogon Lee

Research output: Contribution to journalArticle

131 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)417-430
Number of pages14
JournalMolecular cell
Volume36
Issue number3
DOIs
StatePublished - Nov 13 2009

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Keywords

  • MOLNEURO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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