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Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II)

Type IA topoisomerase activities are essential for resolving DNA topological barriers via an enzyme-mediated transient single strand DNA break. Accumulation of topoisomerase DNA cleavage product can lead to cell death or genomic rearrangement. Many antibacterial and anticancer drugs act as topoisome...

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Autores principales: Cheng, Bokun, Annamalai, Thirunavukkarasu, Sandhaus, Shayna, Bansod, Priyanka, Tse-Dinh, Yuk-Ching
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370478/
https://www.ncbi.nlm.nih.gov/pubmed/25798600
http://dx.doi.org/10.1371/journal.pone.0120022
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author Cheng, Bokun
Annamalai, Thirunavukkarasu
Sandhaus, Shayna
Bansod, Priyanka
Tse-Dinh, Yuk-Ching
author_facet Cheng, Bokun
Annamalai, Thirunavukkarasu
Sandhaus, Shayna
Bansod, Priyanka
Tse-Dinh, Yuk-Ching
author_sort Cheng, Bokun
collection PubMed
description Type IA topoisomerase activities are essential for resolving DNA topological barriers via an enzyme-mediated transient single strand DNA break. Accumulation of topoisomerase DNA cleavage product can lead to cell death or genomic rearrangement. Many antibacterial and anticancer drugs act as topoisomerase poison inhibitors that form stabilized ternary complexes with the topoisomerase covalent intermediate, so it is desirable to identify such inhibitors for type IA topoisomerases. Here we report that organomercury compounds were identified during a fluorescence based screening of the NIH diversity set of small molecules for topoisomerase inhibitors that can increase the DNA cleavage product of Yersinia pestis topoisomerase I. Inhibition of relaxation activity and accumulation of DNA cleavage product were confirmed for these organomercury compounds in gel based assays of Escherichia coli topoisomerase I. Hg(II), but not As(III), could also target the cysteines that form the multiple Zn(II) binding tetra-cysteine motifs found in the C-terminal domains of these bacterial topoisomerase I for relaxation activity inhibition. Mycobacterium tuberculosis topoisomerase I activity is not sensitive to Hg(II) or the organomercury compounds due to the absence of the Zn(II) binding cysteines. It is significant that the type IA topoisomerases with Zn(II) binding domains can still cleave DNA when interfered by Hg(II) or organomercury compounds. The Zn(II) binding domains found in human Top3α and Top3β may be potential targets of toxic metals and organometallic complexes, with potential consequence on genomic stability and development.
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spelling pubmed-43704782015-04-04 Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II) Cheng, Bokun Annamalai, Thirunavukkarasu Sandhaus, Shayna Bansod, Priyanka Tse-Dinh, Yuk-Ching PLoS One Research Article Type IA topoisomerase activities are essential for resolving DNA topological barriers via an enzyme-mediated transient single strand DNA break. Accumulation of topoisomerase DNA cleavage product can lead to cell death or genomic rearrangement. Many antibacterial and anticancer drugs act as topoisomerase poison inhibitors that form stabilized ternary complexes with the topoisomerase covalent intermediate, so it is desirable to identify such inhibitors for type IA topoisomerases. Here we report that organomercury compounds were identified during a fluorescence based screening of the NIH diversity set of small molecules for topoisomerase inhibitors that can increase the DNA cleavage product of Yersinia pestis topoisomerase I. Inhibition of relaxation activity and accumulation of DNA cleavage product were confirmed for these organomercury compounds in gel based assays of Escherichia coli topoisomerase I. Hg(II), but not As(III), could also target the cysteines that form the multiple Zn(II) binding tetra-cysteine motifs found in the C-terminal domains of these bacterial topoisomerase I for relaxation activity inhibition. Mycobacterium tuberculosis topoisomerase I activity is not sensitive to Hg(II) or the organomercury compounds due to the absence of the Zn(II) binding cysteines. It is significant that the type IA topoisomerases with Zn(II) binding domains can still cleave DNA when interfered by Hg(II) or organomercury compounds. The Zn(II) binding domains found in human Top3α and Top3β may be potential targets of toxic metals and organometallic complexes, with potential consequence on genomic stability and development. Public Library of Science 2015-03-23 /pmc/articles/PMC4370478/ /pubmed/25798600 http://dx.doi.org/10.1371/journal.pone.0120022 Text en © 2015 Cheng et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cheng, Bokun
Annamalai, Thirunavukkarasu
Sandhaus, Shayna
Bansod, Priyanka
Tse-Dinh, Yuk-Ching
Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II)
title Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II)
title_full Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II)
title_fullStr Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II)
title_full_unstemmed Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II)
title_short Inhibition of Zn(II) Binding Type IA Topoisomerases by Organomercury Compounds and Hg(II)
title_sort inhibition of zn(ii) binding type ia topoisomerases by organomercury compounds and hg(ii)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370478/
https://www.ncbi.nlm.nih.gov/pubmed/25798600
http://dx.doi.org/10.1371/journal.pone.0120022
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