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

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dc.contributor.author Wei, Ting
dc.contributor.author Najmi, Saman M.
dc.contributor.author Liu, Hester
dc.contributor.author Peltonen, Karita
dc.contributor.author Kucerova, Alena
dc.contributor.author Schneider, David A.
dc.contributor.author Laiho, Marikki
dc.date.accessioned 2018-04-27T08:04:01Z
dc.date.available 2018-04-27T08:04:01Z
dc.date.issued 2018-04-10
dc.identifier.citation 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
dc.identifier.other PURE: 103550963
dc.identifier.other PURE UUID: 2759d909-592c-46e3-92d4-823bf22f326c
dc.identifier.other RIS: urn:0DB0930C98107F8D2B27638971487CF4
dc.identifier.other WOS: 000429866600007
dc.identifier.other Scopus: 85045021180
dc.identifier.other ORCID: /0000-0002-3063-451X/work/44189199
dc.identifier.uri http://hdl.handle.net/10138/234589
dc.description.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. en
dc.format.extent 11
dc.language.iso eng
dc.relation.ispartof Cell Reports
dc.rights cc_by_nc_nd
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject transcription
dc.subject elongation
dc.subject cancer therapeutics
dc.subject rRNA
dc.subject nucleolus
dc.subject yeast
dc.subject G-QUADRUPLEX
dc.subject CANCER
dc.subject MACHINERY
dc.subject PROMOTER
dc.subject PATHWAY
dc.subject STRESS
dc.subject GENES
dc.subject STEPS
dc.subject DRUG
dc.subject P53
dc.subject 317 Pharmacy
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint en
dc.type Article
dc.contributor.organization Faculty of Pharmacy
dc.contributor.organization Division of Pharmaceutical Biosciences
dc.contributor.organization Institute of Biotechnology
dc.contributor.organization Drug Research Program
dc.contributor.organization ImmunoViroTherapy Lab
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1016/j.celrep.2018.03.066
dc.relation.issn 2211-1247
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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