Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint.
Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint.
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DOI：
10.1016/j.celrep.2018.03.066
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发表时间：
2018-04-10
期刊：
影响因子：
8.8
通讯作者：
Laiho M
中科院分区：
文献类型：
--
作者：
Wei T;Najmi SM;Liu H;Peltonen K;Kucerova A;Schneider DA;Laiho M
RNA聚合酶I（Pol I）的抑制是现代癌症治疗的有前途的策略。BMH-21是一类抑制Pol I转录并诱导酶降解的小分子，但这种特殊的反应是如何实施的尚不清楚。在这里，我们定义了响应所需的关键要素。我们发现Pol I前起始因子和聚合酶亚基（例如，RPA 135）是BMH-21介导的RPA 194降解所必需的。我们进一步发现BMH-21对Pol I的抑制和诱导降解在酵母中是保守的。遗传分析表明，突变，诱导转录延伸缺陷的Pol I导致超敏反应BMH-21。使用完全重建的Pol I转录测定，我们表明BMH-21直接损害Pol I的转录延伸，导致长寿命的聚合酶暂停。这些研究定义了一个保守的监管检查点，监测Pol I转录，并通过治疗干预激活。目前正在探索RNA聚合酶I的靶向用于癌症治疗。Wei等人表明，小分子BMH-21激活了一个保守的RNA聚合酶I检查点，该检查点监测转录效率。BMH-21的转录抑制和检查点激活使聚合酶与染色质脱离并导致酶破坏。
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. Targeting of RNA polymerase I is currently being explored for cancer therapeutics. Wei et al. show that small-molecule BMH-21 activates a conserved RNA polymerase I checkpoint that monitors efficiency of transcription. Transcription inhibition and checkpoint activation by BMH-21 disengages the polymerase from chromatin and causes enzyme destruction.
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影响因子：
5.4
作者：
Grummt, Ingrid
通讯作者：
Grummt, Ingrid
影响因子：
3.7
作者：
Popov, Alexey;Smirnov, Evgeny;Raska, Ivan
通讯作者：
Raska, Ivan
DOI：
10.1073/pnas.0406746101
发表时间：
2004-10-19
影响因子：
11.1
作者：
Schneider, DA;Nomura, M
通讯作者：
Nomura, M
抑制RNA聚合酶I作为促进p53癌症特异性激活的治疗策略。
影响因子：
50.3
作者：
Bywater MJ;Poortinga G;Sanij E;Hein N;Peck A;Cullinane C;Wall M;Cluse L;Drygin D;Anderes K;Huser N;Proffitt C;Bliesath J;Haddach M;Schwaebe MK;Ryckman DM;Rice WG;Schmitt C;Lowe SW;Johnstone RW;Pearson RB;McArthur GA;Hannan RD
通讯作者：
Hannan RD
影响因子：
8.8
作者：
Viktorovskaya OV;Engel KL;French SL;Cui P;Vandeventer PJ;Pavlovic EM;Beyer AL;Kaplan CD;Schneider DA
通讯作者：
Schneider DA