Cell：超时的昼夜节律科学家通过基因突变使昼夜节律延长

生物谷

生物谷报道：以往科学家对昼夜节律进行了大量的研究，发现了昼夜节律实际上一个复杂的基因调控系统，包括clock, per, time等一系列基因相互作用的结果。

在本期Cell上封面文章报道了美国西北大学霍华德休斯医学研究所（Howard Hughes Medical Institute）Joseph S. Takahashi教授的最新发现，通过ENU（生物谷注：一种可以广泛导致基因随机突变的药物）使小鼠基因随机突变，从其中筛选出一种昼夜节律在26小时左右的昼夜节律突变型小鼠，称之为“超时小鼠”，同时筛选出阳性克隆，并进行了遗传学深入分析。实际上这种超时小鼠的原因在于F-box蛋白FBXL3上一个位点出现突变，使第364个氨基酸编码从异亮氨基酸改变成苏氨酸，从而使该蛋白失去功能。在这种小鼠上，Period基因表达的两种蛋白PER1和PER2都下降了，然而CRY基因表达的CRY1和CRY2没有改变。但是，FBXL3功能的丢失，使CRY蛋白更稳定，这导致了Per和Cry基因整体转录的抑制，从而出现了昼夜节律的延长。这也表明，FBXL3是导致昼夜节律延长的主要因素。

英文摘要：

Using a forward genetics ENU mutagenesis screen for recessive mutations that affect circadian rhythmicity in the mouse, we isolated a long period ( not, vert, similar 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, Fbxl3^Ovtm defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.

原始出处：

Circadian Mutant Overtime Reveals F-box Protein FBXL3 Regulation of Cryptochrome and Period Gene Expression.Sandra M. Siepka¹^,²^,⁵, Seung-Hee Yoo²^,⁵, Junghea Park², Weimin Song¹, Vivek Kumar¹^,², Yinin Hu², Choogon Lee⁴ and Joseph S. Takahashi. Cell, Volume 129, Issue 5, 1 June 2007, Pages 1011-1023