Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors.
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.
Rutter
J
J
Department of Biochemistry, University of Texas-Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152, USA.
Reick
M
M
Wu
L C
LC
McKnight
S L
SL
D056930:ARNTL Transcription Factors; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks; D056926:CLOCK Proteins; D002460:Cell Line; D002940:Circadian Rhythm; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins; D019281:Dimerization; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009243:NAD / Q000378:metabolism* / Q000494:pharmacology; D009249:NADP / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
D056930:ARNTL Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D007770:L-Lactate Dehydrogenase; D009243:NAD; D009249:NADP; D009419:Nerve Tissue Proteins; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C497396:ARNT protein, human; C538960:BMAL1 protein, human; C497397:Arnt protein, mouse; C538961:Bmal1 protein, mouse; C104264:NPAS2 protein, human; C491259:Npas2 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse