Effects of Secondary Metabolites from the Fungus Septofusidium berolinense on DNA Cleavage Mediated by Human Topoisomerase II alpha

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dc.contributor.authorVann, Kendra R.
dc.contributor.authorEkiz, Guener
dc.contributor.authorZencir, Sevil
dc.contributor.authorBedir, Erdal
dc.contributor.authorTopcu, Zeki
dc.contributor.authorOsheroff, Neil
dc.date.accessioned2019-10-27T23:11:05Z
dc.date.available2019-10-27T23:11:05Z
dc.date.issued2016
dc.departmentEge Üniversitesien_US
dc.description.abstractTwo metabolites from the ascomycete fungus Septofusidium berolinense were recently identified as having antineoplastic activity [Ekiz et al. (2015) J. Antibiot., DOI: 10.1038/ja.2015.84]. However, the basis for this activity is not known. One of the compounds [3,6-dihydroxy-2-propylbenzaldehyde (GE-1)] is a hydroquinone, and the other [2-hydroxymethyl-3-propylcyclohexa-2,5-diene-1,4-dione (GE-2)] is a quinone. Because some hydroquinones and quinones act as topoisomerase II poisons, the effects of GE-1 and GE-2 on DNA cleavage mediated by human topoisomerase IIa were assessed. GE-2 enhanced DNA cleavage similar to 4-fold and induced scission with a site specificity similar to that of the anticancer drug etoposide. Similar to other quinone-based topoisomerase II poisons, GE-2 displayed several hallmark characteristics of covalent topoisomerase II poisons, including (1) the inability to poison a topoisomerase IIa construct that lacks the N-terminal domain, (2) the inhibition of DNA cleavage when the compound was incubated with the enzyme prior to the addition of plasmid, and (3) the loss of poisoning activity in the presence of a reducing agent. In contrast to GE-2, GE-1 did not enhance DNA cleavage mediated by topoisomerase IIa except at very high concentrations. However, the activity and potency of the metabolite were dramatically enhanced under oxidizing conditions. These results suggest that topoisomerase IIa may play a role in mediating the cytotoxic effects of these fungal metabolites.en_US
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [GM033944]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [109S361]; EBILTEMEge University [2012/BIL/028]; Turkish Scientific and Technical Research AssemblyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [115Z349]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R25 GM062459, T32 GM008320]en_US
dc.description.sponsorshipThis research was supported by grant GM033944 (N.O.) from the National Institutes of Health, grants from TUBITAK (109S361) and EBILTEM (2012/BIL/028) (E.B.), and grant 115Z349 (Z.T.) from the Turkish Scientific and Technical Research Assembly. K.R.V. was a trainee under NIH grants R25 GM062459 and T32 GM008320 and was supported in part by a Research Supplement to Grant GM033944 to Promote Diversity in Health-Related Research.en_US
dc.identifier.doi10.1021/acs.chemrestox.6b00009en_US
dc.identifier.endpage420en_US
dc.identifier.issn0893-228X
dc.identifier.issn1520-5010
dc.identifier.issue3en_US
dc.identifier.pmid26894873en_US
dc.identifier.startpage415en_US
dc.identifier.urihttps://doi.org/10.1021/acs.chemrestox.6b00009
dc.identifier.urihttps://hdl.handle.net/11454/53015
dc.identifier.volume29en_US
dc.identifier.wosWOS:000372677900019en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Chemical Socen_US
dc.relation.ispartofChemical Research in Toxicologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleEffects of Secondary Metabolites from the Fungus Septofusidium berolinense on DNA Cleavage Mediated by Human Topoisomerase II alphaen_US
dc.typeArticleen_US

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