Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint

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http://hdl.handle.net/10138/234589

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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

Titel: Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint
Författare: Wei, Ting; Najmi, Saman M.; Liu, Hester; Peltonen, Karita; Kucerova, Alena; Schneider, David A.; Laiho, Marikki
Upphovmannens organisation: Faculty of Pharmacy
Division of Pharmaceutical Biosciences
Institute of Biotechnology
Drug Research Program
ImmunoViroTherapy Lab
Datum: 2018-04-10
Språk: eng
Sidantal: 11
Tillhör serie: Cell Reports
ISSN: 2211-1247
DOI: https://doi.org/10.1016/j.celrep.2018.03.066
Permanenta länken (URI): http://hdl.handle.net/10138/234589
Abstrakt: 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
Referentgranskad: Ja
Licens: cc_by_nc_nd
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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