Clerocidin interacts with the cleavage complex of Streptococcus pneumoniae topoisomerase IV to induce selective irreversible DNA damage
Identifieur interne : 001674 ( Main/Exploration ); précédent : 001673; suivant : 001675Clerocidin interacts with the cleavage complex of Streptococcus pneumoniae topoisomerase IV to induce selective irreversible DNA damage
Auteurs : Sara N. Richter [Italie] ; Elisabetta Leo [Italie, Royaume-Uni] ; Giulia Giaretta [Italie] ; Barbara Gatto [Italie] ; L. Mark Fisher [Royaume-Uni] ; Manlio Palumbo [Italie]Source :
- Nucleic Acids Research [ 0305-1048 ] ; 2006.
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 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.
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DOI: 10.1093/nar/gkl127
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Acids Res.</title><idno type="ISSN">0305-1048</idno><idno type="eISSN">1362-4962</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006">2006</date><biblScope unit="volume">34</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="1982">1982</biblScope><biblScope unit="page" to="1991">1991</biblScope></imprint><idno type="ISSN">0305-1048</idno></series><idno type="istex">2A3B13AA32C3984B2B085BEBDE2F8D6D38CAE1BC</idno><idno type="DOI">10.1093/nar/gkl127</idno><idno type="local">gkl127</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0305-1048</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 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.</div></front></TEI><affiliations><list><country><li>Italie</li><li>Royaume-Uni</li></country></list><tree><country name="Italie"><noRegion><name sortKey="Richter, Sara N" sort="Richter, Sara N" uniqKey="Richter S" first="Sara N." last="Richter">Sara N. Richter</name></noRegion><name sortKey="Gatto, Barbara" sort="Gatto, Barbara" uniqKey="Gatto B" first="Barbara" last="Gatto">Barbara Gatto</name><name sortKey="Giaretta, Giulia" sort="Giaretta, Giulia" uniqKey="Giaretta G" first="Giulia" last="Giaretta">Giulia Giaretta</name><name sortKey="Leo, Elisabetta" sort="Leo, Elisabetta" uniqKey="Leo E" first="Elisabetta" last="Leo">Elisabetta Leo</name><name sortKey="Palumbo, Manlio" sort="Palumbo, Manlio" uniqKey="Palumbo M" first="Manlio" last="Palumbo">Manlio Palumbo</name><name sortKey="Palumbo, Manlio" sort="Palumbo, Manlio" uniqKey="Palumbo M" first="Manlio" last="Palumbo">Manlio Palumbo</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Leo, Elisabetta" sort="Leo, Elisabetta" uniqKey="Leo E" first="Elisabetta" last="Leo">Elisabetta Leo</name></noRegion><name sortKey="Fisher, L Mark" sort="Fisher, L Mark" uniqKey="Fisher L" first="L. Mark" last="Fisher">L. 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