Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock.
Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock.
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时钟的双重模式：哺乳动物昼夜节律时钟中由加密斑块和周期蛋白介导的BMAL1抑制作用。
DOI：
10.1101/gad.249417.114
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发表时间：
2014-09-15
影响因子：
10.5
通讯作者：
Sancar A
中科院分区：
文献类型：
--
作者：
Ye R;Selby CP;Chiou YY;Ozkan-Dagliyan I;Gaddameedhi S;Sancar A
哺乳动物生物钟基于转录-翻译反馈环，其中 CLOCK 和 BMAL1 蛋白充当隐花色素和周期基因的转录激活剂，这些基因编码以约 24 小时的周期抑制 CLOCK-BMAL1 的蛋白。叶等人。显示 CRY 在启动子处与 CLOCK-BMAL1 结合并抑制 CLOCK-BMAL1 依赖性转录而不解离复合物。 PER 单独对 CLOCK-BMAL1 激活的转录没有影响，但在 CRY 存在的情况下，PER 进入核通过从启动子中取代 CLOCK-BMAL1 来抑制转录。哺乳动物生物钟基于转录-翻译反馈环路 (TTFL)，其中 CLOCK 和 BMAL1 蛋白充当隐花色素和周期基因的转录激活剂，这些基因编码以约 24 小时为周期抑制 CLOCK-BMAL1 的蛋白。在此模型中，CRY 和 PER 的机制作用尚不清楚。在这里，我们使用受控靶向系统将 CRY1 或 PER2 引入具有明确昼夜节律基因型的小鼠细胞的细胞核中，以表征 CRY 和 PER 的功能。我们的数据表明，CRY 是 TTFL 中的主要阻遏蛋白：它在启动子处与 CLOCK-BMAL1 结合，并抑制 CLOCK-BMAL1 依赖性转录，而不解离复合物（“阻断”型阻遏）。 PER 单独对 CLOCK–BMAL1 激活的转录没有影响。然而，在 CRY 存在的情况下，PER 进入核通过从启动子上置换 CLOCK-BMAL1（“置换”型抑制）来抑制转录。根据这些发现，我们提出了一种哺乳动物生物钟的新模型，其中 TTFL 的负臂在昼夜节律周期中通过两种不同的机制进行。
The mammalian circadian clock is based on a transcription–translation feedback loop in which CLOCK and BMAL1 proteins act as transcriptional activators of Cryptochrome and Period genes, which encode proteins that repress CLOCK–BMAL1 with a periodicity of ∼ 24 h. Ye et al. show that CRY binds to CLOCK–BMAL1 at the promoter and inhibits CLOCK–BMAL1-dependent transcription without dissociating the complex. PER alone has no effect on CLOCK–BMAL1-activated transcription, but in the presence of CRY, nuclear entry of PER inhibits transcription by displacing CLOCK–BMAL1 from the promoter. The mammalian circadian clock is based on a transcription–translation feedback loop (TTFL) in which CLOCK and BMAL1 proteins act as transcriptional activators of Cryptochrome and Period genes, which encode proteins that repress CLOCK–BMAL1 with a periodicity of ∼24 h. In this model, the mechanistic roles of CRY and PER are unclear. Here, we used a controlled targeting system to introduce CRY1 or PER2 into the nuclei of mouse cells with defined circadian genotypes to characterize the functions of CRY and PER. Our data show that CRY is the primary repressor in the TTFL: It binds to CLOCK–BMAL1 at the promoter and inhibits CLOCK–BMAL1-dependent transcription without dissociating the complex (“blocking”-type repression). PER alone has no effect on CLOCK–BMAL1-activated transcription. However, in the presence of CRY, nuclear entry of PER inhibits transcription by displacing CLOCK–BMAL1 from the promoter (“displacement”-type repression). In light of these findings, we propose a new model for the mammalian circadian clock in which the negative arm of the TTFL proceeds by two different mechanisms during the circadian cycle.
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影响因子：
25
作者：
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通讯作者：
Sassone-Corsi, Paolo
影响因子：
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