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Metal Exchange in the Interprotein Zn II -Binding Site of the Rad50 Hook Domain : Structural Insights into Cd II-Induced DNA-Repair Inhibition

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cris.lastimport.scopus2024-02-12T19:29:44Z
dc.abstract.enCdII is a major genotoxic agent that readily displaces ZnII in a multitude of zinc proteins, abrogates redox homeostasis, and deregulates cellular metalloproteome. To date, this displacement has been described mostly for cysteine(Cys)-rich intraprotein binding sites in certain zinc finger domains and metallothioneins. To visualize how a ZnII-to-CdII swap can affect the target protein's status and thus understand the molecular basis of CdII-induced genotoxicity an intermolecular ZnII-binding site from the crucial DNA repair protein Rad50 and its zinc hook domain were examined. By using a length-varied peptide base, ZnII-to-CdII displacement in Rad50’s hook domain is demonstrated to alter it in a bimodal fashion: 1) CdII induces around a two-orders-of-magnitude stabilization effect (log urn:x-wiley:09476539:media:chem201904942:chem201904942-math-0001 =20.8 vs. log urn:x-wiley:09476539:media:chem201904942:chem201904942-math-0002 =22.7), which defines an extremely high affinity of a peptide towards a metal ion, and 2) the displacement disrupts the overall assembly of the domain, as shown by NMR spectroscopic and anisotropy decay data. Based on the results, a new model explaining the molecular mechanism of CdII genotoxicity that underlines CdII’s impact on Rad50’s dimer stability and quaternary structure that could potentially result in abrogation of the major DNA damage response pathway is proposed.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorKerber, Olga
dc.contributor.authorMaciejczyk, Maciej
dc.contributor.authorPadjasek, Michał
dc.contributor.authorPyrka, Maciej
dc.contributor.authorNowakowski, Michał
dc.contributor.authorKrężel, Artur
dc.contributor.authorKoźmiński, Wiktor
dc.date.accessioned2024-01-25T11:27:55Z
dc.date.available2024-01-25T11:27:55Z
dc.date.copyright2020-07-02
dc.date.issued2020
dc.date.openaccess1
dc.description.accesstimeAFTER_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.versionFINAL_PUBLISHED
dc.description.volume26
dc.identifier.doi10.1002/CHEM.201904942
dc.identifier.issn0947-6539
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/112330
dc.identifier.weblinkhttps://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/chem.201904942
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofChemistry - A European Journal
dc.relation.pages3297-3313
dc.rightsCC-BY
dc.sciencecloudnosend
dc.titleMetal Exchange in the Interprotein Zn II -Binding Site of the Rad50 Hook Domain : Structural Insights into Cd II-Induced DNA-Repair Inhibition
dc.typeJournalArticle
dspace.entity.typePublication