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

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)404-414
Number of pages11
JournalCell Reports
Volume23
Issue number2
DOIs
StatePublished - Apr 10 2018

    Fingerprint

Keywords

  • cancer therapeutics
  • elongation
  • nucleolus
  • rRNA
  • transcription
  • yeast

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this