Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint
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 requis...
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Veröffentlicht in: | Cell reports (Cambridge) 2018-04, Vol.23 (2), p.404-414 |
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Sprache: | eng |
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Zusammenfassung: | 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.
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•BMH-21 is an RNA polymerase I elongation inhibitor•Its activity as a polymerase inhibitor is conserved in yeast•Degradation of the largest subunit reveals a transcription checkpoint•Elongation defects sensitize cells to polymerase inhibition
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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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2018.03.066 |