The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancer.
The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancer.
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FMR1 mRNA中含有FMRP结合位点的G-四分之一是一种有效的外部剪接增强子。
DOI：
10.1093/nar/gkn472
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发表时间：
2008-09
影响因子：
14.9
通讯作者：
Moine, Herve
中科院分区：
文献类型：
--
作者：
Didiot, Marie-Cecile;Tian, Zhaoxia;Schaeffer, Celine;Subramanian, Murugan;Mandel, Jean-Louis;Moine, Herve
脆性 X 智力迟钝蛋白 (FMRP) 是一种 RNA 结合蛋白，旨在转录后调节对神经元发育和突触可塑性重要的基因的表达。我们之前证明 FMRP 通过鸟嘌呤四联体 (G-四联体) RNA 基序与其自身的 FMR1 mRNA 结合。然而，这种结合对 FMR1 表达的功能影响尚未确定。在这项工作中，我们通过定点诱变方法表征了 FMR1 mRNA 内的 FMRP 结合位点 (FBS)，并研究了其对 FMR1 表达的重要性。我们发现，FMR1 mRNA 中的 FBS 采用两种可供 FMRP 同等结合的 G 四重体结构。虽然 FMRP 与 mRNA 的结合通常被认为会诱导翻译调节，但我们发现抑制与 FMRP 结合的 FMR1 mRNA 突变不会影响其在细胞模型中的翻译。相反，我们证明胎牛血清是小基因系统中有效的外显子剪接增强子。此外，FMR1 选择性剪接受细胞内 FMRP 水平的影响。这些数据表明，FMR1 mRNA 中存在的 G 四联体基序可以充当负向自动调节环中其选择性剪接的控制元件。
The fragile X mental retardation protein (FMRP) is a RNA-binding protein proposed to post-transcriptionally regulate the expression of genes important for neuronal development and synaptic plasticity. We previously demonstrated that FMRP binds to its own FMR1 mRNA via a guanine-quartet (G-quartet) RNA motif. However, the functional effect of this binding on FMR1 expression was not established. In this work, we characterized the FMRP binding site (FBS) within the FMR1 mRNA by a site directed mutagenesis approach and we investigated its importance for FMR1 expression. We show that the FBS in the FMR1 mRNA adopts two alternative G-quartet structures to which FMRP can equally bind. While FMRP binding to mRNAs is generally proposed to induce translational regulation, we found that mutations in the FMR1 mRNA suppressing binding to FMRP do not affect its translation in cellular models. We show instead that the FBS is a potent exonic splicing enhancer in a minigene system. Furthermore, FMR1 alternative splicing is affected by the intracellular level of FMRP. These data suggest that the G-quartet motif present in the FMR1 mRNA can act as a control element of its alternative splicing in a negative autoregulatory loop.
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影响因子：
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