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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
SGUL Authors: Fisher, Larry Mark

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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
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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
Related URLs:
1 January 2006Published
Web of Science ID: WOS:000237522900009
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