The BMAL1 C terminus regulates the circadian transcription feedback loop
The BMAL1 C terminus regulates the circadian transcription feedback loop
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DOI：
10.1073/pnas.0601416103
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发表时间：
2006-06-27
影响因子：
11.1
通讯作者：
Yagita, Kazuhiro
中科院分区：
文献类型：
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作者：
Kiyohara, Yota B.;Tagao, Sayaka;Yagita, Kazuhiro
生物钟由细胞自主转录/翻译反馈回路驱动。BMAL 1转录因子是哺乳动物中这一分子振荡器的正臂的不可或缺的组成部分。在这里，我们提出了一个突变的生物钟蛋白的分子遗传学筛选试验，是基于培养的成纤维细胞的实时昼夜节律监测。通过使用这种方法，我们确定了BMAL 1的极端C末端的一个结构域，它在E盒介导的昼夜节律转录的节律控制中起着至关重要的作用。值得注意的是，BMAL 1的最后43个aa是转录激活以及与昼夜节律转录抑制子CRYPTOCHROME 1（CRY 1）结合所需的，具体取决于CLOCK蛋白的共存。C-末端截短的BMAL 1突变体蛋白仍然与mPER 2（负反馈环的另一种蛋白质）相关联，这表明另外的抑制机制可能集中在N末端。综上所述，这些结果表明，BMAL 1的C-末端区域参与决定昼夜转录激活和抑制之间的平衡。
The circadian clock is driven by cell-autonomous transcription/translation feedback loops. The BMAL1 transcription factor is an indispensable component of the positive arm of this molecular oscillator in mammals. Here, we present a molecular genetic screening assay for mutant circadian clock proteins that is based on real-time circadian rhythm monitoring in cultured fibroblasts. By using this assay, we identified a domain in the extreme C terminus of BMAL1 that plays an essential role in the rhythmic control of E-box-mediated circadian transcription. Remarkably, the last 43 aa of BMAL1 are required for transcriptional activation, as well as for association with the circadian transcriptional repressor CRYPTOCHROME 1 (CRY1), depending on the coexistence of CLOCK protein. C-terminally truncated BMAL1 mutant proteins still associate with mPER2 (another protein of the negative feedback loop), suggesting that an additional repression mechanism may converge on the N terminus. Taken together, these results suggest that the C-terminal region of BMAL1 is involved in determining the balance between circadian transcriptional activation and suppression.