TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA.
TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA.
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DOI：
10.15252/embj.201488740
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发表时间：
2014-12-17
期刊：
影响因子：
--
通讯作者：
Link CD
中科院分区：
文献类型：
--
作者：
Saldi TK;Ash PE;Wilson G;Gonzales P;Garrido-Lecca A;Roberts CM;Dostal V;Gendron TF;Stein LD;Blumenthal T;Petrucelli L;Link CD
缺失TDP-1（神经变性相关RNA结合蛋白TDP-43的直系同源物）的秀丽隐杆线虫突变体仅显示轻度表型。然而，转录组测序显示，许多RNA在突变体中的积累和/或加工发生了改变。对这些转录异常的分析表明，TDP-1的主要功能是限制双链RNA的形成或稳定性。具体地说，我们发现tdp-1的缺失：（1）优先改变具有固有双链结构的RNA（dsRNA）的积累;（2）增加核dsRNA灶的积累;（3）增加腺苷到肌苷RNA编辑的频率;（4）增加核内的RNA聚集;（5）增加核内的RNA聚集。和（4）显著增加可与dsRNA特异性抗体免疫沉淀的转录物的量，包括内含子序列，反义RNA与另一个转录物和转座子重叠。我们还表明，人类细胞中的SDP-43敲低会导致双链RNA的积累，这表明抑制双链RNA是哺乳动物中SDP-43的保守功能。结构化RNA的改变的积累可以解释一些先前描述的分子表型（例如，剪接改变），这是由于TDP-43功能降低所致。
Caenorhabditis elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA-binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP-1 is to limit formation or stability of double-stranded RNA. Specifically, we found that deletion of tdp-1: (1) preferentially alters the accumulation of RNAs with inherent double-stranded structure (dsRNA); (2) increases the accumulation of nuclear dsRNA foci; (3) enhances the frequency of adenosine-to-inosine RNA editing; and (4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA-specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP-43 knockdown in human cells results in accumulation of dsRNA, indicating that suppression of dsRNA is a conserved function of TDP-43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP-43 function.
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通讯作者：
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