Wei , T , Najmi , S M , Liu , H , Peltonen , K , Kucerova , A , Schneider , D A & Laiho , M 2018 , ' Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint ' , Cell Reports , vol. 23 , no. 2 , pp. 404-414 . https://doi.org/10.1016/j.celrep.2018.03.066
Title: | Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint |
Author: | Wei, Ting; Najmi, Saman M.; Liu, Hester; Peltonen, Karita; Kucerova, Alena; Schneider, David A.; Laiho, Marikki |
Contributor organization: | Faculty of Pharmacy Division of Pharmaceutical Biosciences Institute of Biotechnology Drug Research Program ImmunoViroTherapy Lab |
Date: | 2018-04-10 |
Language: | eng |
Number of pages: | 11 |
Belongs to series: | Cell Reports |
ISSN: | 2211-1247 |
DOI: | https://doi.org/10.1016/j.celrep.2018.03.066 |
URI: | http://hdl.handle.net/10138/234589 |
Abstract: | Summary 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. |
Subject: |
transcription
elongation cancer therapeutics rRNA nucleolus yeast G-QUADRUPLEX CANCER MACHINERY PROMOTER PATHWAY STRESS GENES STEPS DRUG P53 317 Pharmacy 1182 Biochemistry, cell and molecular biology |
Peer reviewed: | Yes |
Rights: | cc_by_nc_nd |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
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