The killing of African trypanosomes by ethidium bromide.

Introduced in the 1950s, ethidium bromide (EB) is still used as an anti-trypanosomal drug for African cattle although its mechanism of killing has been unclear and controversial. EB has long been known to cause loss of the mitochondrial genome, named kinetoplast DNA (kDNA), a giant network of interl...

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Autores principales:	Arnab Roy Chowdhury, Rahul Bakshi, Jianyang Wang, Gokben Yildirir, Beiyu Liu, Valeria Pappas-Brown, Gökhan Tolun, Jack D Griffith, Theresa A Shapiro, Robert E Jensen, Paul T Englund
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fb8e2012b7964a0091c8eb39ae88ecf7
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spelling	oai:doaj.org-article:fb8e2012b7964a0091c8eb39ae88ecf72021-11-18T06:03:43ZThe killing of African trypanosomes by ethidium bromide.1553-73661553-737410.1371/journal.ppat.1001226https://doaj.org/article/fb8e2012b7964a0091c8eb39ae88ecf72010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21187912/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Introduced in the 1950s, ethidium bromide (EB) is still used as an anti-trypanosomal drug for African cattle although its mechanism of killing has been unclear and controversial. EB has long been known to cause loss of the mitochondrial genome, named kinetoplast DNA (kDNA), a giant network of interlocked minicircles and maxicircles. However, the existence of viable parasites lacking kDNA (dyskinetoplastic) led many to think that kDNA loss could not be the mechanism of killing. When recent studies indicated that kDNA is indeed essential in bloodstream trypanosomes and that dyskinetoplastic cells survive only if they have a compensating mutation in the nuclear genome, we investigated the effect of EB on kDNA and its replication. We here report some remarkable effects of EB. Using EM and other techniques, we found that binding of EB to network minicircles is low, probably because of their association with proteins that prevent helix unwinding. In contrast, covalently-closed minicircles that had been released from the network for replication bind EB extensively, causing them, after isolation, to become highly supertwisted and to develop regions of left-handed Z-DNA (without EB, these circles are fully relaxed). In vivo, EB causes helix distortion of free minicircles, preventing replication initiation and resulting in kDNA loss and cell death. Unexpectedly, EB also kills dyskinetoplastic trypanosomes, lacking kDNA, by inhibiting nuclear replication. Since the effect on kDNA occurs at a >10-fold lower EB concentration than that on nuclear DNA, we conclude that minicircle replication initiation is likely EB's most vulnerable target, but the effect on nuclear replication may also contribute to cell killing.Arnab Roy ChowdhuryRahul BakshiJianyang WangGokben YildirirBeiyu LiuValeria Pappas-BrownGökhan TolunJack D GriffithTheresa A ShapiroRobert E JensenPaul T EnglundPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 12, p e1001226 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Arnab Roy Chowdhury Rahul Bakshi Jianyang Wang Gokben Yildirir Beiyu Liu Valeria Pappas-Brown Gökhan Tolun Jack D Griffith Theresa A Shapiro Robert E Jensen Paul T Englund The killing of African trypanosomes by ethidium bromide.
description	Introduced in the 1950s, ethidium bromide (EB) is still used as an anti-trypanosomal drug for African cattle although its mechanism of killing has been unclear and controversial. EB has long been known to cause loss of the mitochondrial genome, named kinetoplast DNA (kDNA), a giant network of interlocked minicircles and maxicircles. However, the existence of viable parasites lacking kDNA (dyskinetoplastic) led many to think that kDNA loss could not be the mechanism of killing. When recent studies indicated that kDNA is indeed essential in bloodstream trypanosomes and that dyskinetoplastic cells survive only if they have a compensating mutation in the nuclear genome, we investigated the effect of EB on kDNA and its replication. We here report some remarkable effects of EB. Using EM and other techniques, we found that binding of EB to network minicircles is low, probably because of their association with proteins that prevent helix unwinding. In contrast, covalently-closed minicircles that had been released from the network for replication bind EB extensively, causing them, after isolation, to become highly supertwisted and to develop regions of left-handed Z-DNA (without EB, these circles are fully relaxed). In vivo, EB causes helix distortion of free minicircles, preventing replication initiation and resulting in kDNA loss and cell death. Unexpectedly, EB also kills dyskinetoplastic trypanosomes, lacking kDNA, by inhibiting nuclear replication. Since the effect on kDNA occurs at a >10-fold lower EB concentration than that on nuclear DNA, we conclude that minicircle replication initiation is likely EB's most vulnerable target, but the effect on nuclear replication may also contribute to cell killing.
format	article
author	Arnab Roy Chowdhury Rahul Bakshi Jianyang Wang Gokben Yildirir Beiyu Liu Valeria Pappas-Brown Gökhan Tolun Jack D Griffith Theresa A Shapiro Robert E Jensen Paul T Englund
author_facet	Arnab Roy Chowdhury Rahul Bakshi Jianyang Wang Gokben Yildirir Beiyu Liu Valeria Pappas-Brown Gökhan Tolun Jack D Griffith Theresa A Shapiro Robert E Jensen Paul T Englund
author_sort	Arnab Roy Chowdhury
title	The killing of African trypanosomes by ethidium bromide.
title_short	The killing of African trypanosomes by ethidium bromide.
title_full	The killing of African trypanosomes by ethidium bromide.
title_fullStr	The killing of African trypanosomes by ethidium bromide.
title_full_unstemmed	The killing of African trypanosomes by ethidium bromide.
title_sort	killing of african trypanosomes by ethidium bromide.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/fb8e2012b7964a0091c8eb39ae88ecf7
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The killing of African trypanosomes by ethidium bromide.

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