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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Specific binding of RNA polymerase Ⅱ to the human immunodeficiency virus trans-activating region RNA is regulated by cellular cofactors and Tat
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Specific binding of RNA polymerase Ⅱ to the human immunodeficiency virus trans-activating region RNA is regulated by cellular cofactors and Tat

机译：RNA聚合酶Ⅱ与人免疫缺陷病毒反式激活区的特异性结合受细胞因子和Tat的调控

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摘要

The regulation of human immunodeficiency virus type 1 (HIV-1) gene expression in response to Tat is dependent on an element downstream of the HIV-1 transcriptional initiation site designated the trans-activating region (TAR). TAR forms a stable stem-loop RNA structure in which a 3-nt bulge structure and a 6-nt loop structure are important for Tat activation. In the absence of Tat, the HIV-1 promoter generates so-called short or nonprocessive transcripts terminating at +60, while in the presence of Tat the synthesis of these short transcripts is markedly decreased and transcripts that extend through the 9.0-kb HIV-1 genome are synthesized. Tat effects on transcriptional elongation are likely due to alterations in the elongation properties of RNA polymerase Ⅱ. In this study we demonstrated that a set of cellular cofactors that modulate the binding of the cellular protein TRP-185 to the TAR RNA loop sequences also functioned to markedly stimulate the specific binding of hypophosphorylated (IIa) and hyperphosphorylated (IIo) RNA polymerase Ⅱ to TAR RNA. The concentrations of RNA polymerase Ⅱ required for this interaction with TAR RNA were similar to those required to initiate in vitro transcription from the HIV-1 long terminal repeat. RNA gel retardation analysis with wild-type and mutant TAR RNAs indicated that the TAR RNA loop and bulge sequences were critical for the binding of RNA polymerase Ⅱ. The addition of wild-type but not mutant Tat protein to gel retardation analysis with TAR RNA and RNA polymerase Ⅱ resulted in the loss of binding of RNA polymerase Ⅱ binding to TAR RNA. These results suggest that Tat may function to alter RNA polymerase Ⅱ, which is paused due to its binding to HIV-1 TAR RNA with resultant stimulation of its transcriptional elongation properties.
机译：响应Tat的人类免疫缺陷病毒1型（HIV-1）基因表达的调节取决于被称为反式激活区（TAR）的HIV-1转录起始位点下游的元件。 TAR形成稳定的茎环RNA结构，其中3-nt凸起结构和6-nt环结构对于Tat激活很重要。在没有Tat的情况下，HIV-1启动子会生成所谓的短或非过程性转录物，终止于+60，而在Tat存在时，这些短转录物的合成显着减少，并且转录物延伸至9.0-kb HIV-合成了1个基因组。 Tat对转录伸长的影响可能是由于RNA聚合酶Ⅱ伸长特性的改变。在这项研究中，我们证明了一组调节细胞蛋白TRP-185与TAR RNA环序列结合的细胞辅因子，还可以显着刺激次磷酸化（IIa）和超磷酸化（IIo）RNA聚合酶Ⅱ与TAR RNA。与TAR RNA相互作用所需的RNA聚合酶Ⅱ的浓度类似于从HIV-1长末端重复序列开始体外转录所需的浓度。野生型和突变型TAR RNA的RNA凝胶阻滞分析表明，TAR RNA环和凸起序列对于RNA聚合酶Ⅱ的结合至关重要。在TAR RNA和RNA聚合酶Ⅱ的凝胶阻滞分析中加入野生型而不是突变型Tat蛋白，导致RNA聚合酶Ⅱ与TAR RNA的结合丧失。这些结果表明，Tat可能具有改变RNA聚合酶Ⅱ的作用，该酶由于与HIV-1 TAR RNA结合而被暂停，从而刺激了其转录延伸特性。

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