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首页> 外文期刊>Molecular and Cellular Biology >Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo
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Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo

机译：人体组装的端粒酶全酶亚基相互作用的特异性和化学计量

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The H/ACA motif of human telomerase RNA (hTR) directs specific pathways of endogenous telomerase holoenzyme assembly, function, and regulation. Similarities between hTR and other H/ACA RNAs have been established, but differences have not been explored even though unique features of hTR H/ACA RNP assembly give rise to telomerase deficiency in human disease. Here, we define hTR H/ACA RNA and RNP architecture using RNA accumulation, RNP affinity purification, and primer extension activity assays. First, we evaluate alternative folding models for the hTR H/ACA motif 5′ hairpin. Second, we demonstrate an unanticipated and surprisingly general asymmetry of 5′ and 3′ hairpin requirements for H/ACA RNA accumulation. Third, we establish that hTR assembles not one but two sets of all four of the H/ACA RNP core proteins, dyskerin, NOP10, NHP2, and GAR1. Fourth, we address a difference in predicted specificities of hTR association with the holoenzyme subunit WDR79/TCAB1. Together, these results complete the analysis of hTR elements required for active RNP biogenesis and define the interaction specificities and stoichiometries of all functionally essential human telomerase holoenzyme subunits. This study uncovers unexpected similarities but also differences between telomerase and other H/ACA RNPs that allow a unique specificity of telomerase biogenesis and regulation.
机译：人类端粒酶RNA（hTR）的H / ACA主题指导内源端粒酶全酶装配，功能和调节的特定途径。已经建立了hTR和其他H / ACA RNA之间的相似性，但是即使hTR H / ACA RNP装配的独特特征导致人类疾病中的端粒酶缺乏，也没有探讨差异。在这里，我们使用RNA积累，RNP亲和力纯化和引物延伸活性测定法定义hTR H / ACA RNA和RNP结构。首先，我们评估hTR H / ACA主题5'发夹的替代折叠模型。其次，我们证明了H / ACA RNA积累的5'和3'发夹要求的出乎意料且令人惊讶的普遍不对称性。第三，我们确定hTR组装的不是H / ACA RNP核心蛋白中的全部四个，即dyskerin，NOP10，NHP2和GAR1中的两个而是两个。第四，我们解决了与全酶亚基WDR79 / TCAB1在hTR关联的预测特异性方面的差异。总之，这些结果完成了活性RNP生物发生所需的hTR元素的分析，并定义了所有功能必需的人类端粒酶全酶亚基的相互作用特异性和化学计量。这项研究发现了意料之外的相似之处，但也发现了端粒酶与其他H / ACA RNP之间的差异，这些差异使得端粒酶的生物发生和调控具有独特的特异性。

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