Cryo-EM structures of human RNA polymerase III in its unbound and transcribing states

IF 16.8 1区 生物学
M. Girbig, A. Misiaszek, Matthias K. Vorländer, Aleix Lafita, H. Grötsch, F. Baudin, A. Bateman, C. Müller
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引用次数: 40

Abstract

RNA polymerase III (Pol III) synthesizes transfer RNAs and other short, essential RNAs. Human Pol III misregulation is linked to tumor transformation, neurodegenerative and developmental disorders, and increased sensitivity to viral infections. Here, we present cryo-electron microscopy structures at 2.8 to 3.3 Å resolution of transcribing and unbound human Pol III. We observe insertion of the TFIIS-like subunit RPC10 into the polymerase funnel, providing insights into how RPC10 triggers transcription termination. Our structures resolve elements absent from Saccharomyces cerevisiae Pol III such as the winged-helix domains of RPC5 and an iron–sulfur cluster, which tethers the heterotrimer subcomplex to the core. The cancer-associated RPC7α isoform binds the polymerase clamp, potentially interfering with Pol III inhibition by tumor suppressor MAF1, which may explain why overexpressed RPC7α enhances tumor transformation. Finally, the human Pol III structure allows mapping of disease-related mutations and may contribute to the development of inhibitors that selectively target Pol III for therapeutic interventions. Cryo-EM structures of human Pol III in both apo- and elongating states reveal metazoan-specific differences in the regulation of transcription termination and identify mutations relevant to human disease.
人RNA聚合酶III非结合状态和转录状态的低温电镜结构
RNA聚合酶III (RNA polymerase III, Pol III)合成转移RNA和其他短而必需的RNA。人类Pol III的失调与肿瘤转化、神经退行性和发育障碍以及对病毒感染的敏感性增加有关。在这里,我们展示了2.8至3.3 Å分辨率的转录和未结合的人Pol III的低温电镜结构。我们观察到tfiis样亚基RPC10插入到聚合酶漏斗中,为RPC10如何触发转录终止提供了见解。我们的结构解决了酿酒酵母Pol III中缺乏的元素,如RPC5的翼状螺旋结构域和铁硫簇,它将异源三聚体亚络合物连接到核心。癌症相关的RPC7α亚型结合聚合酶钳,可能干扰肿瘤抑制因子MAF1对Pol III的抑制,这可能解释了为什么过表达的RPC7α促进肿瘤转化。最后,人类Pol III结构允许绘制疾病相关突变,并可能有助于开发选择性靶向Pol III进行治疗干预的抑制剂。人类Pol III在载子状态和延长状态下的低温电镜结构揭示了转录终止调控的后生动物特异性差异,并鉴定了与人类疾病相关的突变。
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来源期刊
Nature Structural &Molecular Biology
Nature Structural &Molecular Biology 生物-生化与分子生物学
自引率
1.80%
发文量
160
期刊介绍: Nature Structural & Molecular Biology is a monthly journal that focuses on the functional and mechanistic understanding of how molecular components in a biological process work together. It serves as an integrated forum for structural and molecular studies. The journal places a strong emphasis on the functional and mechanistic understanding of how molecular components in a biological process work together. Some specific areas of interest include the structure and function of proteins, nucleic acids, and other macromolecules, DNA replication, repair and recombination, transcription, regulation of transcription and translation, protein folding, processing and degradation, signal transduction, and intracellular signaling.
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