Article: article from journal or magazin.
SIRT1 regulates circadian clock gene expression through PER2 deacetylation.
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.
ARNTL Transcription Factors, Acetylation, Animals, Basic Helix-Loop-Helix Transcription Factors/metabolism, CLOCK Proteins, Cell Cycle Proteins/metabolism, Cells, Cultured, Circadian Rhythm, Embryo, Mammalian/cytology, Fibroblasts/metabolism, Gene Expression Regulation, Liver/metabolism, Mice, NIH 3T3 Cells, Nuclear Proteins/metabolism, Period Circadian Proteins, Sirtuin 1, Sirtuins/metabolism, Trans-Activators/metabolism, Transcription Factors/metabolism
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