Ishizuka Akira, Siomi Mikiko C, Siomi Haruhiko
Institute for Genome Research, Graduate School of Nutrition, University of Tokushima, Tokushima 770-8503, Japan.
Genes Dev. 2002 Oct 1;16(19):2497-508. doi: 10.1101/gad.1022002.
Fragile X syndrome is a common form of inherited mental retardation caused by the loss of FMR1 expression. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. In Drosophila, the fly homolog of the FMR1 protein (dFMR1) binds to and represses the translation of an mRNA encoding of the microtuble-associated protein Futsch. We have isolated a dFMR1-associated complex that includes two ribosomal proteins, L5 and L11, along with 5S RNA. The dFMR1 complex also contains Argonaute2 (AGO2) and a Drosophila homolog of p68 RNA helicase (Dmp68). AGO2 is an essential component for the RNA-induced silencing complex (RISC), a sequence-specific nuclease complex that mediates RNA interference (RNAi) in Drosophila. We show that Dmp68 is also required for efficient RNAi. We further show that dFMR1 is associated with Dicer, another essential component of the RNAi pathway, and microRNAs (miRNAs) in vivo, suggesting that dFMR1 is part of the RNAi-related apparatus. Our findings suggest a model in which the RNAi and dFMR1-mediated translational control pathways intersect in Drosophila. Our findings also raise the possibility that defects in an RNAi-related machinery may cause human disease.
脆性X综合征是一种常见的遗传性智力障碍，由FMR1表达缺失引起。FMR1基因编码一种RNA结合蛋白，该蛋白与正在翻译的核糖体结合，并作为负性翻译调节因子发挥作用。在果蝇中，FMR1蛋白的果蝇同源物（dFMR1）结合并抑制编码微管相关蛋白Futsch的mRNA的翻译。我们分离出了一种与dFMR1相关的复合物，其中包括两种核糖体蛋白L5和L11以及5S RNA。dFMR1复合物还包含Argonaute2（AGO2）和p68 RNA解旋酶的果蝇同源物（Dmp68）。AGO2是RNA诱导沉默复合物（RISC）的重要组成部分，RISC是一种序列特异性核酸酶复合物，介导果蝇中的RNA干扰（RNAi）。我们发现Dmp68对于有效的RNAi也是必需的。我们进一步表明，dFMR1在体内与RNAi途径的另一个重要组成部分Dicer以及微小RNA（miRNA）相关联，这表明dFMR1是RNAi相关机制的一部分。我们的研究结果提出了一个模型，即RNAi和dFMR1介导的翻译控制途径在果蝇中相交。我们的研究结果还增加了一种可能性，即RNAi相关机制的缺陷可能导致人类疾病。
