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Clerocidin interacts with the cleavage complex of Streptococcus pneumoniae topoisomerase IV to induce selective irreversible DNA damage

Richter, SN; Leo, E; Giaretta, G; Gatto, B; Fisher, LM; Palumbo, M (2006) Clerocidin interacts with the cleavage complex of Streptococcus pneumoniae topoisomerase IV to induce selective irreversible DNA damage. NUCLEIC ACIDS RESEARCH, 34 (7). 1982 - 1991. ISSN 0305-1048 https://doi.org/10.1093/nar/gkl127
SGUL Authors: Fisher, Larry Mark

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Abstract

Clerocidin (CL), a diterpenoid natural product, alkylates DNA through its epoxide moiety and exhibits both anticancer and antibacterial activities. We have examined CLaction in the presence of topoisomerase IV from Streptococcus pneumoniae. CL promoted irreversible enzyme-mediated DNA cleavage leading to single- and double-stranded DNA breaks at specific sites. Reaction required the diterpenoid function: no cleavage was seen using a naphthalene-substituted analogue. Moreover, drug-induced DNA breakage was not observed using a mutant topoisomerase IV (ParC Y118F) unable to form a cleavage complex with DNA. Sequenceanalysis of 102 single-stranded DNA breaks and 79 double-stranded breaks revealed an overwhelming preference for G at the �1 position, i.e. immediately 50 of the enzyme DNA scission site. This specificity contrasts with that of topoisomerase IV cleavage with antibacterial quinolones. Indeed, CL stimulated DNA breakage by a quinolone-resistant topoisomerase IV (ParC S79F). Overall, the results indicate that topoisomerase IV facilitates selective irreversible CL attack at guanine and that its cleavage complex differs markedly from that of mammalian topoisomerase II which promotes both irreversible and reversible CL attack at guanine and cytosine, respectively. The unique ability to form exclusively irreversible DNA breaks suggests topoisomerase IV may be a key intracellular target of CL in bacteria.

Item Type: Article
Additional Information: Copyright: The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Keywords: Amino Acid Substitution, Anti-Bacterial Agents, DNA Damage, DNA Topoisomerase IV, DNA, Bacterial, Diterpenes, Drug Resistance, Bacterial, Enzyme Inhibitors, Guanine, Quinolones, Streptococcus pneumoniae, Substrate Specificity, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, BIOCHEMISTRY & MOLECULAR BIOLOGY, II TOPOISOMERASES, ESCHERICHIA-COLI, ENZYME-DNA, WILD-TYPE, GYRASE, SEQUENCE, FLUOROQUINOLONES, DETERMINANTS, QUINOLONES, MECHANISM, Developmental Biology, 05 Environmental Sciences, 06 Biological Sciences, 08 Information And Computing Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: NUCLEIC ACIDS RESEARCH
ISSN: 0305-1048
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Dates:
DateEvent
1 January 2006Published
Web of Science ID: WOS:000237522900009
URI: http://openaccess.sgul.ac.uk/id/eprint/107081
Publisher's version: https://doi.org/10.1093/nar/gkl127

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