Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis
| Autor: | Donald P Cameron, Ross D. Hannan, Gloria Rudenko, James Budzak, Gretchen Poortinga, Elaine E Pegg, Katherine M. Hannan, Louise Kerry |
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| Přispěvatelé: | Wellcome Trust |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Transcription Genetic Nucleolus Toxicology Pathology and Laboratory Medicine Biochemistry Polymerases Epithelium chemistry.chemical_compound 0302 clinical medicine Animal Cells RNA Polymerase I Transcription (biology) RNA polymerase Medicine and Health Sciences Transcriptional regulation Enzyme Inhibitors Connective Tissue Cells Protozoans Cytotoxicity Assay biology lcsh:Public aspects of medicine 11 Medical And Health Sciences Trypanocidal Agents 3. Good health Nucleic acids Infectious Diseases Ribosomal RNA Connective Tissue 030220 oncology & carcinogenesis Cellular Structures and Organelles Cellular Types Anatomy Research Article Trypanosoma lcsh:Arctic medicine. Tropical medicine lcsh:RC955-962 DNA transcription Trypanosoma brucei brucei Trypanosoma brucei RNA polymerase III Inhibitory Concentration 50 03 medical and health sciences Tropical Medicine DNA-binding proteins parasitic diseases Genetics RNA polymerase I Non-coding RNA Cell Nucleus Organisms Public Health Environmental and Occupational Health Biology and Life Sciences Proteins lcsh:RA1-1270 Epithelial Cells Cell Biology Processivity Fibroblasts 06 Biological Sciences biology.organism_classification Molecular biology Parasitic Protozoans Biological Tissue Trypanosomiasis African 030104 developmental biology chemistry RNA Gene expression Ribosomes Trypanosoma Brucei Gambiense |
| Zdroj: | PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 11, Iss 3, p e0005432 (2017) |
| Popis: | 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. Author summary Trypanosoma brucei is protected by an essential Variant Surface Glycoprotein (VSG) coat in the mammalian bloodstream. The active VSG gene is transcribed by RNA polymerase I (Pol I), which typically only transcribes rDNA. Pol I transcription inhibitors are under clinical trials for cancer chemotherapy. As T. brucei relies on Pol I for VSG transcription, we investigated its susceptibility to these drugs. We show that quarfloxin (CX-3543), CX-5461, and BMH-21 are effective against T. brucei at nanomolar concentrations. T. brucei death was due to rapid and specific inhibition of Pol I transcription. Incubation with Pol I transcription inhibitors also resulted in disappearance of Pol I subnuclear structures like the nucleolus and the VSG expression site body (ESB). Rapid ESB loss followed the Pol I transcription block, arguing that the ESB is nucleated by Pol I transcription. Pol I transcription inhibitors could therefore potentially function as novel drugs against trypanosomiasis. |
| Databáze: | OpenAIRE |
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