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

Nucleic Acids Research
Sara N RichterM Palumbo

Abstract

Clerocidin (CL), a diterpenoid natural product, alkylates DNA through its epoxide moiety and exhibits both anticancer and antibacterial activities. We have examined CL action 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. Sequence analysis of 102 single-stranded DNA breaks and 79 double-stranded breaks revealed an overwhelming preference for G at the -1 position, i.e. immediately 5' 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 att...Continue Reading

References

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Jan 18, 1996·Nature·J M BergerJ C Wang
Dec 6, 1996·The Journal of Biological Chemistry·C Ullsperger, N R Cozzarelli
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Oct 21, 2004·Nucleic Acids Research·Sara N RichterManlio Palumbo

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Citations

Sep 10, 2011·Applied Microbiology and Biotechnology·Frédéric CollinAnthony Maxwell
Mar 31, 2007·Mechanisms of Ageing and Development·Torsten RichterThomas von Zglinicki
Feb 20, 2009·Organic & Biomolecular Chemistry·Sara N RichterManlio Palumbo
Aug 1, 2009·EcoSal Plus·Katherine Evans-Roberts, Anthony Maxwell
Oct 6, 2015·EcoSal Plus·Natassja G BushAnthony Maxwell

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Methods Mentioned

BETA
column chromatography
PCR
electrophoresis

Software Mentioned

Bio
Rad ImageQuant
ImageQuant

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