ArticlePLoS neglected tropical diseases2017
Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis.
Article in PLoS neglected tropical diseases, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 41 citations in OpenAlex.
- An Improved Method for the Isolation of Extrachromosomal DNA from the Pathogenic Free-Living AmoebaMethods and protocols · 2026Article
- Genome-wide mapping of DNA G-quadruplexes in Trypanosoma brucei chromatin reveals enrichment in coding regions and transcription start sites.Nucleic acids research · 2026Article
- RNA Polymerase 1 inhibitors against African trypanosomesAntimicrobial agents and chemotherapy · 2026Article
- Kinetoplast-Directed Therapies: A Selective Mitochondrial Approach to Combat Leishmaniasis.Pharmaceuticals (Basel, Switzerland) · 2026Review
- The ribosomal RNA transcription landscapes of Plasmodium falciparum and related apicomplexan parasites.Nucleic acids research · 2025Review
- Suppression by RNA Polymerase I Inhibitors Varies Greatly Between Distinct RNA Polymerase I Transcribed Genes in Malaria Parasites.Pathogens (Basel, Switzerland) · 2024Article
- Suppression by RNA Polymerase I Inhibitors Varies Greatly Between Distinct RNA Polymerase I Transcribed Genes in Malaria Parasites.bioRxiv : the preprint server for biology · 2024Article
- Protein phosphatase PP1 regulation of RNA polymerase II transcription termination and allelic exclusion of VSG genes in trypanosomes.Nucleic acids research · 2024Article
- Imaging of genomic loci in Trypanosoma brucei using an optimised LacO-LacI system.Molecular and biochemical parasitology · 2023Article
- Effects of the G-quadruplex-binding drugs quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum.International journal for parasitology. Drugs and drug resistance · 2023Article
- G-Quadruplexes as Key Transcriptional Regulators in Neglected Trypanosomatid Parasites.Chembiochem : a European journal of chemical biology · 2023Review
- The RNA export factor TbMex67 connects transcription and RNA export in Trypanosoma brucei and sets boundaries for RNA polymerase I.Nucleic acids research · 2023Article
- Curvicollide D Isolated from the FungusInternational journal of molecular sciences · 2022Article
- Major Achievements in the Design of Quadruplex-Interactive Small Molecules.Pharmaceuticals (Basel, Switzerland) · 2022Review
- An assembly of nuclear bodies associates with the active VSG expression site in African trypanosomes.Nature communications · 2022Article
- DNA Intercalators Inhibit Eukaryotic Ribosomal RNA Synthesis by Impairing the Initiation of Transcription.Genes · 2021Article
- The establishment of variant surface glycoprotein monoallelic expression revealed by single-cell RNA-seq of Trypanosoma brucei in the tsetse fly salivary glands.PLoS pathogens · 2021Article
- TbTRF suppresses the TERRA level and regulates the cell cycle-dependent TERRA foci number with a TERRA binding activity in its C-terminal Myb domain.Nucleic acids research · 2021Article
- Synthesis and evaluation of bis(imino)anthracene derivatives as G-quadruplex ligands.RSC medicinal chemistry · 2021Article
- Identifying and validating the presence of Guanine-Quadruplexes (G4) within the blood fluke parasite Schistosoma mansoni.PLoS neglected tropical diseases · 2021Article
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8 authors at 2 institutions in 2 countries.
Funding
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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