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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Wei T,Najmi SM,Liu H,Peltonen K,Kucerova A,Schneider DA,Laiho Mdoi
10.1016/j.celrep.2018.03.066subject
Has Abstractpub_date
2018-04-10 00:00:00pages
404-414issue
2issn
2211-1247pii
S2211-1247(18)30427-3journal_volume
23pub_type
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