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

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Title: Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis.
Authors: Kerry, LE
Pegg, EE
Cameron, DP
Budzak, J
Poortinga, G
Hannan, KM
Hannan, RD
Rudenko, G
Item Type: Journal Article
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.
Issue Date: 6-May-2017
Date of Acceptance: 23-Feb-2017
URI: http://hdl.handle.net/10044/1/45863
DOI: https://dx.doi.org/10.1371/journal.pntd.0005432
ISSN: 1935-2735
Publisher: Public Library of Science
Journal / Book Title: PLOS Neglected Tropical Diseases
Volume: 11
Issue: 3
Copyright Statement: © 2017 Kerry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricte d use, distribu tion, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 095161/Z/10/Z
Keywords: Tropical Medicine
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Conference Place: United States
Open Access location: http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005432
Article Number: e0005432
Appears in Collections:Faculty of Natural Sciences



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