Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock
Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock
复制标题
FBXL3 在哺乳动物昼夜节律反馈环路中的双重作用对于周期确定和时钟的鲁棒性非常重要
DOI：
10.1073/pnas.1302560110
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发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Xu, Ying
中科院分区：
文献类型：
--
作者：
Shi, Guangsen;Xing, Lijuan;Xu, Ying
哺乳动物生物钟由相互关联的反馈回路组成。隐花色素是核心负反馈回路中的一个关键成分，而核受体家族成员Rev - Erbα则是相互关联回路的一个重要组成部分。为了解不同生物钟基因的作用，我们通过培育单突变和双突变小鼠进行了基因相互作用筛选。我们发现，在F - box/富含亮氨酸重复序列蛋白（Fbxl3）缺陷小鼠中Rev - erbα的缺失挽救了其长生物钟周期表型，并且我们的研究结果进一步表明，FBXL3通过使Rev - Erbα：组蛋白去乙酰化酶3辅阻遏物复合物失活来调节Rev - Erb/视黄酸受体相关孤儿受体结合元件（RRE）介导的转录。通过分析Fbxl3和隐花色素1双突变小鼠，我们发现FBXL3还调节E - box驱动的基因表达的幅度。FBXL3在生物钟反馈回路中的这两种不同作用提供了一种有助于确定生物钟周期和增强其稳健性的机制。
The mammalian circadian clock is composed of interlocking feedback loops. Cryptochrome is a central component in the core negative feedback loop, whereas Rev-Erb alpha, a member of the nuclear receptor family, is an essential component of the interlocking loop. To understand the roles of different clock genes, we conducted a genetic interaction screen by generating single- and double-mutant mice. We found that the deletion of Rev-erb alpha in F-box/leucine rich-repeat protein (Fbxl3)-deficient mice rescued its long-circadian period phenotype, and our results further revealed that FBXL3 regulates RevErb/retinoic acid receptor-related orphan receptor-binding element (RRE)-mediated transcription by inactivating the Rev-Erba: histone deacetylase 3 corepressor complex. By analyzing the Fbxl3 and Cryptochrome 1 double-mutantmice, we found that FBXL3 also regulates the amplitudes of E-box-driven gene expression. These two separate roles of FBXL3 in circadian feedback loops provide a mechanism that contributes to the period determination and robustness of the clock.