Abstract

At the core of the mammalian circadian clock is a feedback loop in which the heterodimeric transcription factor CLOCK–Brain, Muscle Arnt-like-1 (BMAL1) drives expression of its negative regulators, periods (PERs) and cryptochromes (CRYs). Here, we provide evidence that CLOCK-Interacting Protein, Circadian (CIPC) is an additional negative-feedback regulator of the circadian clock. CIPC exhibits circadian regulation in multiple tissues, and it is a potent and specific inhibitor of CLOCK–BMAL1 activity that functions independently of CRYs. CIPC–CLOCK protein complexes are present in vivo, and depletion of endogenous CIPC shortens the circadian period length. CIPC is unrelated to known proteins and has no recognizable homologues outside vertebrates. Our results suggest that negative feedback in the mammalian circadian clock is divided into distinct pathways, and that the addition of new genes has contributed to the complexity of vertebrate clocks.

1. Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
2. Laboratory of Chronobiology, Institute of Medical Immunology, Schumann Str. 20-21. Charité-Universitaetsmedizin-Berlin, 10098 Berlin, Germany.
3. Current address: Department of Immunology, University of Toronto, Toronto, 1 King's College Circle, Ontario, M5S 1A8, Canada.
4. Current address: Dana Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
5. Current address: Global Prior Art, Inc., 21 Milk St., Boston, MA 02109, USA.
6. Current address: The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Correspondence to: Charles J. Weitz¹ e-mail: cweitz@hms.harvard.edu

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