Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors
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.
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In vivo NAD levels are subjected to daily variations, thereby giving rhythmic input to the genetic clock.
“Interestingly, in vivo NAD levels are subjected to daily variations, thereby giving rhythmic input to the genetic clock [44–46]”
From Circadian control of glucose metabolism (2014) · cites this paper as [45]
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- Authors
- Rutter, J., Reick, M., Wu, L. C., & McKnight, S. L.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Rutter, Jared
- Reick, Martin
- McKnight, Steven L.
- Venue
- Science
- Published
- 2001-07-20
- Volume
- 293
- Issue
- 5529
- Pages
- 510-514
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2063041018
- Cited by
- 1,059
- References
- 39
- Citations by year
- 2026: 26 · 2025: 26 · 2024: 28 · 2023: 32 · 2022: 32 · 2021: 32 · 2020: 40 · 2019: 26 · 2018: 38 · 2017: 42 · 2016: 39 · 2015: 42 · 2014: 44 · 2013: 68 · 2012: 42
- FWCI
- 18.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH059388, 1RO1MH59388)
- National Institute of General Medical Sciences (NIH5-T32-GM08-291-12)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- circadian clock, NPAS2, Bmal1, clocks, NAD+ cofactor, redox state, DNA binding, transcription factor heterodimer, NADPH, NADH, clock entrainment, food entrainment, neuronal activity
- MeSH terms
- Animals, Biological Clocks, Cell Line, Circadian Rhythm, DNA, DNA-Binding Proteins, Humans, L-Lactate Dehydrogenase, NAD, NADP, Nerve Tissue Proteins, Oxidation-Reduction, Recombinant Proteins, Transcription Factors, Trans-Activators, Helix-Loop-Helix Motifs, Receptors, Aryl Hydrocarbon, Dimerization, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Proteins, CLOCK Proteins, ARNTL Transcription Factors
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