SIRT1 regulates circadian clock gene expression through PER2 deacetylation
- PMID: 18662546
- DOI: 10.1016/j.cell.2008.06.050
SIRT1 regulates circadian clock gene expression through PER2 deacetylation
Abstract
The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus of the brain that synchronizes countless subsidiary oscillators in peripheral tissues. The rhythm-generating mechanism is thought to rely on a feedback loop involving positively and negatively acting transcription factors. BMAL1 and CLOCK activate the expression of Period (Per) and Cryptochrome (Cry) genes, and once PER and CRY proteins accumulate to a critical level they form complexes with BMAL1-CLOCK heterodimers and thereby repress the transcription of their own genes. Here, we show that SIRT1, an NAD(+)-dependent protein deacetylase, is required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Rorgamma, Per2, and Cry1. SIRT1 binds CLOCK-BMAL1 in a circadian manner and promotes the deacetylation and degradation of PER2. Given the NAD(+) dependence of SIRT1 deacetylase activity, it is likely that SIRT1 connects cellular metabolism to the circadian core clockwork circuitry.
Comment in
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SIRT1 is a circadian deacetylase for core clock components.Cell. 2008 Jul 25;134(2):212-4. doi: 10.1016/j.cell.2008.07.010. Cell. 2008. PMID: 18662537 Free PMC article.
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Circadian genetics: an enzymatic rheostat.Nat Rev Genet. 2008 Sep;9(9):653. doi: 10.1038/nrg2436. Nat Rev Genet. 2008. PMID: 21491641 No abstract available.
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