Division of Pharmaceutical Biosciences, Faculty of Pharmacy and Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Cell Rep. 2018 Apr 10;23(2):404-414. doi: 10.1016/j.celrep.2018.03.066.
Inhibition of RNA polymerase I (Pol I) is a promising strategy for modern cancer therapy. BMH-21 is a first-in-class small molecule that inhibits Pol I transcription and induces degradation of the enzyme, but how this exceptional response is enforced is not known. Here, we define key elements requisite for the response. We show that Pol I preinitiation factors and polymerase subunits (e.g., RPA135) are required for BMH-21-mediated degradation of RPA194. We further find that Pol I inhibition and induced degradation by BMH-21 are conserved in yeast. Genetic analyses demonstrate that mutations that induce transcription elongation defects in Pol I result in hypersensitivity to BMH-21. Using a fully reconstituted Pol I transcription assay, we show that BMH-21 directly impairs transcription elongation by Pol I, resulting in long-lived polymerase pausing. These studies define a conserved regulatory checkpoint that monitors Pol I transcription and is activated by therapeutic intervention.
抑制 RNA 聚合酶 I（Pol I）是现代癌症治疗的一种有前途的策略。BMH-21 是一种首创的小分子，可抑制 Pol I 转录并诱导酶降解，但尚不清楚这种特殊反应是如何产生的。在这里，我们定义了响应所需的关键要素。我们表明，Pol I 起始前复合物因子和聚合酶亚基（例如，RPA135）是 BMH-21 介导的 RPA194 降解所必需的。我们进一步发现，Pol I 抑制和 BMH-21 诱导的降解在酵母中是保守的。遗传分析表明，诱导 Pol I 转录延伸缺陷的突变会导致对 BMH-21 的敏感性增加。使用完全重建的 Pol I 转录测定法，我们表明 BMH-21 直接损害 Pol I 的转录延伸，导致聚合酶长时间暂停。这些研究定义了一个保守的调控检查点，该检查点可监测 Pol I 的转录，并可通过治疗干预而被激活。
Zotero 插件
