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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

Ting Wei, Saman M Najmi, Hester Liu, Karita Peltonen, Alena Kucerova, David A Schneider, Marikki Laiho

Cell Rep. 2018 Apr 10;23(2):404-414.

PMID: 29642000

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP896705161	BMH-21		896705-16-1	Price

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