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    Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis

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    Author
    Kerry, LE; Pegg, EE; Cameron, DP; Budzak, J; Poortinga, G; Hannan, KM; Hannan, RD; Rudenko, G
    Date
    2017-03-01
    Source Title
    PLoS Neglected Tropical Diseases
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Poortinga, Gretchen; Hannan, Katherine; Hannan, Ross; Cameron, Donald
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Biochemistry and Molecular Biology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Kerry, L. E., Pegg, E. E., Cameron, D. P., Budzak, J., Poortinga, G., Hannan, K. M., Hannan, R. D. & Rudenko, G. (2017). Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. PLOS NEGLECTED TROPICAL DISEASES, 11 (3), https://doi.org/10.1371/journal.pntd.0005432.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258266
    DOI
    10.1371/journal.pntd.0005432
    NHMRC Grant code
    NHMRC/1053792
    NHMRC/1022402
    Abstract
    Trypanosoma brucei relies on an essential Variant Surface Glycoprotein (VSG) coat for survival in the mammalian bloodstream. High VSG expression within an expression site body (ESB) is mediated by RNA polymerase I (Pol I), which in other eukaryotes exclusively transcribes ribosomal RNA genes (rDNA). As T. brucei is reliant on Pol I for VSG transcription, we investigated Pol I transcription inhibitors for selective anti-trypanosomal activity. The Pol I inhibitors quarfloxin (CX-3543), CX-5461, and BMH-21 are currently under investigation for treating cancer, as rapidly dividing cancer cells are particularly dependent on high levels of Pol I transcription compared with nontransformed cells. In T. brucei all three Pol I inhibitors have IC50 concentrations for cell proliferation in the nanomolar range: quarfloxin (155 nM), CX-5461 (279 nM) or BMH-21 (134 nM) compared with IC50 concentrations in the MCF10A human breast epithelial cell line (4.44 μM, 6.89 μM or 460 nM, respectively). T. brucei was therefore 29-fold more sensitive to quarfloxin, 25-fold more sensitive to CX-5461 and 3.4-fold more sensitive to BMH-21. Cell death in T. brucei was due to rapid inhibition of Pol I transcription, as within 15 minutes treatment with the inhibitors rRNA precursor transcript was reduced 97-98% and VSG precursor transcript 91-94%. Incubation with Pol I transcription inhibitors also resulted in disintegration of the ESB as well as the nucleolus subnuclear structures, within one hour. Rapid ESB loss following the block in Pol I transcription argues that the ESB is a Pol I transcription nucleated structure, similar to the nucleolus. In addition to providing insight into Pol I transcription and ES control, Pol I transcription inhibitors potentially also provide new approaches to treat trypanosomiasis.

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