Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets
Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets
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DOI：
10.1016/j.molcel.2007.01.031
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发表时间：
2007-02-23
期刊：
影响因子：
16
通讯作者：
Krzyzosiak, Wlodzimierz J.
中科院分区：
文献类型：
--
作者：
Krol, Jacelk;Fiszer, Agnieszka;Krzyzosiak, Wlodzimierz J.
核糖核酸酶 Dicer 在细胞中发挥作用，从其前体中切除 microRNA，并将长双链 RNA 加工成短干扰 RNA。我们发现含有由 CNG 重复组成的长发夹结构的转录本是另一类 Dicer 靶标。参与三联体重复扩增疾病（例如 1 型强直性肌营养不良、亨廷顿病和 1 型脊髓小脑共济失调）的突变基因的转录本的细胞水平受到 Dicer 的控制。强直性肌营养不良细胞中 Dicer 诱导的突变转录物下调伴随着含有长互补重复序列的转录物下调。由长重复发夹产生的短 CUG 重复充当 siRNA，并使用 RNA 干扰途径触发下游沉默效应。我们证明，由重复组成的合成寡核苷酸在沉默含有互补重复的突变转录物方面具有高度特异性，并且可以被视为潜在的治疗剂。
Ribonuclease Dicer functions in cells to excise microRNAs from their precursors and process long double-stranded RNAs into short interfering RNAs. We show that transcripts containing long hairpin structures composed of CNG repeats are another class of Dicer targets. The cellular levels of transcripts from mutant genes involved in triplet repeat expansion diseases such as myotonic dystrophy type 1, Huntington's disease, and spinocerebellar ataxia type 1 are under Dicer control. The Dicer-induced downregulation of the mutant transcript in myotonic dystrophy cells is accompanied by the downregulation of transcripts containing long complementary repeats. Short CUG repeats generated from long repeat hairpins act as siRNAs and use the RNA interference pathway to trigger the downstream silencing effects. We demonstrate that synthetic oligonucleotides composed of repeats are highly specific in the silencing of mutant transcripts containing complementary repeats and may be considered as potential therapeutic agents.