Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau
Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau
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DOI：
10.1126/science.288.5465.483
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发表时间：
2000-04-21
期刊：
影响因子：
56.9
通讯作者：
Takahashi, JS
中科院分区：
文献类型：
--
作者：
Lowrey, PL;Shimomura, K;Takahashi, JS
Tau突变是一种半显性常染色体等位基因，它显著缩短了叙利亚仓鼠的昼夜节律周期长度。我们报道了使用遗传指导的代表性差异分析来确定仓鼠与老鼠和人类基因组的保守同步区的tau基因座的分子鉴定。Tau基因由果蝇昼夜节律基因Double-time的同源基因酪蛋白激酶I epsilon(CKL Epsilon)编码。野生型和tau突变型CKL epsilon酶的体外表达和功能研究表明，突变型CKL epsilon酶的最大速度和自磷酸化状态明显降低。此外，在体外，CKL epsilon可以与哺乳动物周期蛋白相互作用，而突变的酶缺乏对周期蛋白的磷酸化能力。我们得出结论，tau是仓鼠CKL epsilon的一个等位基因，并提出了该突变导致突变动物的昼夜节律异常表型的机制。
The tau mutation is a semidominant autosomal allele that dramatically shortens period Length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau Locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau Locus is encoded by casein kinase I epsilon (CKl epsilon), a homolog of the Drosophila circadian gene double-time. in vitro expression and functional studies of wild-type and tau mutant CKl epsilon enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKl epsilon can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKl epsilon and propose a mechanism by which the mutation Leads to the observed aberrant circadian phenotype in mutant animals.