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Differential roles of human Dicer-binding proteins TRBP and PACT in small RNA processing

机译：人类Dicer结合蛋白TRBP和PACT在小RNA加工中的差异作用

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During RNA interference and related gene regulatory pathways, the endonuclease Dicer cleaves precursor RNA molecules to produce microRNAs (miRNAs) and short interfering RNAs (siRNAs). Human cells encode a single Dicer enzyme that can associate with two different double-stranded RNA (dsRNA)-binding proteins, protein activator of PKR (PACT) and trans-activation response RNA-binding protein (TRBP). However, the functional redundancy or differentiation of PACT and TRBP in miRNA and siRNA biogenesis is not well understood. Using a reconstituted system, we show here that PACT and TRBP have distinct effects on Dicer-mediated dsRNA processing. In particular, we found that PACT in complex with Dicer inhibits the processing of pre-siRNA substrates when compared with Dicer and a Dicer–TRBP complex. In addition, PACT and TRBP show non-redundant effects on the production of different-sized miRNAs (isomiRs), which in turn alter target-binding specificities. Experiments using chimeric versions of PACT and TRBP suggest that the two N-terminal RNA-binding domains of each protein confer the observed differences in dsRNA substrate recognition and processing behavior of Dicer–dsRNA-binding protein complexes. These results support the conclusion that in humans, Dicer-associated dsRNA-binding proteins are important regulatory factors that contribute both substrate and cleavage specificity during miRNA and siRNA production.
机译：在RNA干扰和相关基因调控途径中，核酸内切酶Dicer裂解前体RNA分子以产生microRNA（miRNA）和短干扰RNA（siRNA）。人类细胞编码一种单一的Dicer酶，该酶可以与两种不同的双链RNA（dsRNA）结合蛋白，PKR的蛋白激活剂（PACT）和反式激活反应RNA结合蛋白（TRBP）结合。然而，在miRNA和siRNA生物发生中PACT和TRBP的功能冗余或分化尚不清楚。使用重构的系统，我们在这里显示PACT和TRBP对Dicer介导的dsRNA加工具有独特的影响。尤其是，我们发现与Dicer和Dicer–TRBP复合物相比，与Dicer复合物形成的PACT抑制了pre-siRNA底物的加工。此外，PACT和TRBP对不同大小的miRNA（isomiRs）的产生显示出非冗余作用，进而改变了靶标结合特异性。使用PACT和TRBP的嵌合形式进行的实验表明，每种蛋白质的两个N末端RNA结合结构域在dsRNA底物识别和Dicer–dsRNA结合蛋白复合物的加工行为方面具有观察到的差异。这些结果支持以下结论：在人类中，与Dicer相关的dsRNA结合蛋白是重要的调节因子，在miRNA和siRNA产生过程中既贡献了底物，又提供了切割特异性。

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