New Article in Chemistry — A European Journal


Metal exchange in interprotein Zn(II)‐binding site of Rad50 hook domain – structural insights into Cd(II)‐induced DNA repair inhibition

Michał Padjasek, Maciej Maciejczyk, Michał Nowakowski, Olga Kerber, Maciej Pyrka, Wiktor Koźmiński, Artur Krężel


Cd(II) is a major genotoxic agent that readily displaces Zn(II) in a multitude of zinc proteins, abrogates redox homeostasis and deregulates cellular metalloproteome. To date this displacement has been described mostly for cysteine‐rich intraprotein binding sites in certain zinc finger domains and metallothionein. To visualize how Zn(II) to Cd(II) swap can affect the target protein’s status and thus understand the molecular basis of Cd(II)‐induced genotoxicity we focused on an intermolecular Zn(II)‐binding site from the crucial DNA repair protein Rad50 and its zinc hook domain. Using a length‐varied peptide base we hereby demonstrate that Zn(II) to Cd(II) displacement in Rad50’s hook domain alters it in a bimodal fashion: (i) Cd(II) induces around a two‐orders‐of‐magnitude stabilization effect (log K 12 Zn(II) = 20.8 vs log K 12 Cd(II) = 22.7), which defines an extremely high affinity of a peptide towards a metal ion, and (ii) disrupts the overall assembly of the domain, as shown by NMR and anisotropy decay data. Based on our results we propose a novel model explaining the molecular mechanism of Cd(II) genotoxicity that underlines Cd(II)’s impact on Rad50’s dimer stability and quaternary structure that could potentially result in abrogation of the major DNA damage response pathway.


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