Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Science. 2011 Jun 17;332(6036):1436-9. doi: 10.1126/science.1196766.
Circadian rhythms in mammals are generated by a feedback loop in which the three PERIOD (PER) proteins, acting in a large complex, inhibit the transcriptional activity of the CLOCK-BMAL1 dimer, which represses their own expression. Although fundamental, the mechanism of negative feedback in the mammalian clock, or any eukaryotic clock, is unknown. We analyzed protein constituents of PER complexes purified from mouse tissues and identified PSF (polypyrimidine tract-binding protein-associated splicing factor). Our analysis indicates that PSF within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and that the PER complex thereby rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription. These findings provide a function for the PER complex and a molecular mechanism for circadian clock negative feedback.
哺乳动物的昼夜节律是由一个反馈环产生的，其中三种 PERIOD（PER）蛋白在一个大型复合物中起作用，抑制 CLOCK-BMAL1 二聚体的转录活性，从而抑制它们自身的表达。尽管这是基本的，但哺乳动物钟或任何真核钟的负反馈机制尚不清楚。我们分析了从鼠组织中纯化的 PER 复合物的蛋白质成分，并鉴定出 PSF（多嘧啶 tract 结合蛋白相关剪接因子）。我们的分析表明，PER 复合物中的 PSF 招募 SIN3A，这是转录抑制复合物组装的支架，并且 PER 复合物由此将组蛋白去乙酰化酶有节奏地递送到 Per1 启动子，从而抑制 Per1 转录。这些发现为 PER 复合物提供了功能，并为生物钟负反馈提供了分子机制。
