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Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors

Science. 2001 Jul 20;293(5529):510-4. doi: 10.1126/science.1060698. Epub 2001 Jul 5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Basic Helix-Loop-Helix Transcription Factors
  • Biological Clocks
  • CLOCK Proteins
  • Cell Line
  • Circadian Rhythm
  • DNA / metabolism*
  • DNA-Binding Proteins*
  • Dimerization
  • Helix-Loop-Helix Motifs
  • Humans
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Mice
  • NAD / metabolism*
  • NAD / pharmacology
  • NADP / metabolism*
  • NADP / pharmacology
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Oxidation-Reduction
  • Receptors, Aryl Hydrocarbon*
  • Recombinant Proteins / metabolism
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*

Substances

  • ARNT protein, human
  • ARNTL Transcription Factors
  • BMAL1 protein, human
  • Arnt protein, mouse
  • Bmal1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • NPAS2 protein, human
  • Nerve Tissue Proteins
  • Npas2 protein, mouse
  • Receptors, Aryl Hydrocarbon
  • Recombinant Proteins
  • Trans-Activators
  • Transcription Factors
  • NAD
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • NADP
  • DNA
  • L-Lactate Dehydrogenase
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, mouse