Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis.
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)....
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ftdoajarticles:oai:doaj.org/article:4a35b7495b2f4c1d877fe6f8ca6eb7b2 2023-05-15T15:16:48+02:00 Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. Louise E Kerry Elaine E Pegg Donald P Cameron James Budzak Gretchen Poortinga Katherine M Hannan Ross D Hannan Gloria Rudenko 2017-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0005432 https://doaj.org/article/4a35b7495b2f4c1d877fe6f8ca6eb7b2 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5354456?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005432 https://doaj.org/article/4a35b7495b2f4c1d877fe6f8ca6eb7b2 PLoS Neglected Tropical Diseases, Vol 11, Iss 3, p e0005432 (2017) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2017 ftdoajarticles https://doi.org/10.1371/journal.pntd.0005432 2022-12-31T02:26:47Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 11 3 e0005432 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Louise E Kerry Elaine E Pegg Donald P Cameron James Budzak Gretchen Poortinga Katherine M Hannan Ross D Hannan Gloria Rudenko Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Louise E Kerry Elaine E Pegg Donald P Cameron James Budzak Gretchen Poortinga Katherine M Hannan Ross D Hannan Gloria Rudenko |
author_facet |
Louise E Kerry Elaine E Pegg Donald P Cameron James Budzak Gretchen Poortinga Katherine M Hannan Ross D Hannan Gloria Rudenko |
author_sort |
Louise E Kerry |
title |
Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. |
title_short |
Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. |
title_full |
Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. |
title_fullStr |
Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. |
title_full_unstemmed |
Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. |
title_sort |
selective inhibition of rna polymerase i transcription as a potential approach to treat african trypanosomiasis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2017 |
url |
https://doi.org/10.1371/journal.pntd.0005432 https://doaj.org/article/4a35b7495b2f4c1d877fe6f8ca6eb7b2 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 11, Iss 3, p e0005432 (2017) |
op_relation |
http://europepmc.org/articles/PMC5354456?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005432 https://doaj.org/article/4a35b7495b2f4c1d877fe6f8ca6eb7b2 |
op_doi |
https://doi.org/10.1371/journal.pntd.0005432 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
11 |
container_issue |
3 |
container_start_page |
e0005432 |
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1766347089625743360 |