SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation
2008; Cell Press; Volume: 134; Issue: 2 Linguagem: Inglês
10.1016/j.cell.2008.06.050
ISSN1097-4172
AutoresGad Asher, David Gatfield, Markus Stratmann, Hans Reinke, Charna Dibner, Florian Kreppel, Raúl Mostoslavsky, Frederick W. Alt, Ueli Schibler,
Tópico(s)Photoreceptor and optogenetics research
ResumoThe 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.
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