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The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control
Open accessAbstract
Circadian rhythms govern a large array of metabolic and physiological functions. The central clock protein CLOCK has HAT properties. It directs acetylation of histone H3 and of its dimerization partner BMAL1 at Lys537, an event essential for circadian function. We show that the HDAC activity of the NAD(+)-dependent SIRT1 enzyme is regulated in a circadian manner, correlating with rhythmic acetylation of BMAL1 and H3 Lys9/Lys14 at circadian promoters. SIRT1 associates with CLOCK and is recruited to the CLOCK:BMAL1 chromatin complex at circadian promoters. Genetic ablation of the Sirt1 gene or pharmacological inhibition of SIRT1 activity lead to disturbances in the circadian cycle and in the acetylation of H3 and BMAL1. Finally, using liver-specific SIRT1 mutant mice we show that SIRT1 contributes to circadian control in vivo. We propose that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock.
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“The reduced NADH and radiation-induced DNA damage would reduce NAD+ levels (Fig. 3G), which would impair the circadian rhythm system through perturbed Sirt1 regulation of BMAL acetylation (Nakahata et al., 2008).”
From Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact (2020) · cites this paper as Nakahata et al., 2008
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Cites
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Self-citationObesity and Metabolic Syndrome in Circadian Clock Mutant Mice
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Circadian Redox and Metabolic Oscillations in Mammalian Systems
O'Neill, J. S., & Feeney, K. A. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5582 · Cited by 51
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Alageel, A., Tomasi, J., Tersigni, C., Brietzke, E., Zuckerman, H., Subramaniapillai, M., Lee, Y., Iacobucci, M., Rosenblat, J. D., Mansur, R. B., et al. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.05.017 · Cited by 45
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Central Circadian Clock Regulates Energy Metabolism
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The Liver in the Eyes of a Chronobiologist
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Sato, S., & Sassone-Corsi, P. (2019) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.05.010 · Cited by 10
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Metadata
- Authors
- Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., Chen, D., Guarente, L. P., & Sassone-Corsi, P.
- Affiliations
- University of California, Irvine (US)
- Massachusetts Institute of Technology (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 134
- Issue
- 2
- Pages
- 329-340
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3526943
- OpenAlex
- W1994994441
- Cited by
- 1,427
- References
- 74
- Citations by year
- 2026: 55 · 2025: 60 · 2024: 48 · 2023: 58 · 2022: 67 · 2021: 87 · 2020: 89 · 2019: 84 · 2018: 69 · 2017: 87 · 2016: 93 · 2015: 102 · 2014: 83 · 2013: 106 · 2012: 94
- FWCI
- 36.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1842 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research Coordinating Committee
- National Institutes of Health
- National Institute on Aging (R37AG011119)
- National Institute of General Medical Sciences (R01-GM081634-01, R01GM081634)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- SIRT1, NAD+-dependent deacetylase, circadian clock, clock proteins, Bmal1, histone acetylation, histone deacetylation, chromatin remodeling, circadian rhythm, SIRT1 knockout mice, cellular metabolites
- MeSH terms
- Acetylation, Animals, Circadian Rhythm, DNA-Binding Proteins, Embryo, Mammalian, Histones, Liver, Lysine, Mice, Inbred BALB C, NAD, Promoter Regions, Genetic, Transcription Factors, Trans-Activators, Gene Expression, Sirtuins, Chromatin Assembly and Disassembly, Mice, Basic Helix-Loop-Helix Proteins, Sirtuin 1, CLOCK Proteins, ARNTL Transcription Factors
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