Science & Cell：三篇文章介绍小鼠中发现同一个的生理节奏基因
Cell文章讲述，由西北大学Sandra Siepka和Seung-Hee Yoo率领的研究小组也发现了一个会延长生理周期的FBXL3突变，并将其命名为Overtime (Ovtm)。这种小鼠的突变与Science文章报道的突变不是发生在同一个氨基酸上。研究人员还发现FBSL3功能丢失，CRY蛋白会变得稳定，随之抑制几种钟基因转录。
“因为CRY蛋白没有降解，它们抑制CLODK和BMAL驱动的转录，”文章高级作者Joseph Takahashi解释说。下一个任务是寻找通过控制钟蛋白降解而影响生物钟的更多基因。“CRY的例子说明还会有蛋白降解特异调节的其它例子。”
某些调节钟蛋白降解的基因不一定是特异调节生物钟的，但“更有可能是调节蛋白稳定性的因素，”Weaver说，“当然有很多机制修饰这些蛋白和其稳定性。”
英文原文：
Cell, Vol , Issue , published online April 26, 2007
Article
Circadian Mutant Overtime Reveals F-box Protein FBXL3 Regulation of Cryptochrome and Period Gene Expression
Sandra M. Siepka,1,2,5 Seung-Hee Yoo,2,5 Junghea Park,2 Weimin Song,1 Vivek Kumar,1,2 Yinin Hu,2 Choogon Lee,4 and Joseph S. Takahashi1,2,3,
1 Howard Hughes Medical Institute, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA
2 Center for Functional Genomics, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA
3 Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA
4 Department of Biological Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
Corresponding author
Joseph S. Takahashi
j-takahashi@northwestern.edu
Summary
Using a forward genetics ENU mutagenesis screen for recessive mutations that affect circadian rhythmicity in the mouse, we isolated a long period (∼26 hr) circadian mutant named Overtime (Ovtm). Positional cloning and genetic complementation reveal that Ovtm is encoded by the F-box protein FBXL3, a component of the SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligase complex. The Ovtm mutation causes an isoleucine to threonine (I364T) substitution leading to a loss of function in FBXL3, which interacts specifically with the CRYPTOCHROME (CRY) proteins. In Ovtm mice, expression of the PERIOD proteins PER1 and PER2 is reduced; however, the CRY proteins CRY1 and CRY2 are unchanged. The loss of FBXL3 function leads to a stabilization of the CRY proteins, which in turn leads to a global transcriptional repression of the Per and Cry genes. Thus, Fbxl3Ovtm defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.
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