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Science 293 (5529): 510-514

Copyright © 2001 by the American Association for the Advancement of Science

Regulation of Clock and NPAS2 DNA Binding by the Redox State of NAD Cofactors

Jared Rutter,* Martin Reick,* Leeju C. Wu, Steven L. McKnightdagger

Clock:BMAL1 and NPAS2:BMAL1 are heterodimeric transcription factors that control gene expression as a function of the light-dark cycle. Although built to fluctuate at or near a 24-hour cycle, the clock can be entrained by light, activity, or food. Here we show that the DNA-binding activity of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers is regulated by the redox state of nicotinamide adenine dinucleotide (NAD) cofactors in a purified system. The reduced forms of the redox cofactors, NAD(H) and NADP(H), strongly enhance DNA binding of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers, whereas the oxidized forms inhibit. These observations raise the possibility that food, neuronal activity, or both may entrain the circadian clock by direct modulation of cellular redox state.

Department of Biochemistry, University of Texas-Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: smckni{at}

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