Interaction of Copper(I) with Nucleic Acids

Abstract

Poly(dG-dC) and poly(I) form particularly stable complexes with Cu(I): thus characteristic UV absorbance changes enabled demonstration of Cu(I) transfer from poly(dA-dT) to poly(dG-dC), or from DNA to poly(I). Using pulse radiolysis to generate Cu(I), a rate constant of approximately 4 x 10(7) dm3 mol-1 s-1 (per base unit) was estimated for association of Cu(I) to native DNA, and slightly higher values were found for poly(dA-dT), poly(C), poly(dG-dC) and poly(G). For native DNA and for the models poly(dA-dT) and poly(dG-dC) the addition of Cu(I) was followed by secondary absorbance changes in the time scale of 10 ms, probably due to internal Cu(I) transfer; such secondary reactions were not detectable in heat-denatured DNA or in the homopolymers of A, C, G, and I. Extraction of Cu(I) from the DNA by EDTA is slow, 0.019 s-1, and independent of EDTA concentration, indicating that dissociation of the DNA-Cu(I) complex is the rate-determining step. A tentative value can hence be given for the DNA-Cu(I) stability constant: K = k (forward)/k (reverse) approximately 2 x 10(9) dm3 mol-1. Addition of H2O2 to solutions of gamma-radiolytically generated DNA-Cu(I), at Cu(I)/base less than 0.01, resulted in DNA degradation, comparable in yield to .OH-induced degradation. In the case of poly(dA-dT) and poly(dG-dC) the reaction of H2O2 with the corresponding Cu(I) complexes produced even more damage than the reaction of .OH. The formation of DNA-Cu(I), and the deleterious reaction with H2O2, were hardly affected by RNase or BSA, when added at equal (w/v) concentration. Dismutation of O2.- by (Cu,Zn)-SOD was partly inhibited by DNA and even more by poly(I) at pH 4.4, but not at pH 7, probably by competitive complexation of Cu(I), occurring in the catalytic cycle of SOD.

DNA degradation by the mixture of copper and catechol is caused by DNA-copper-hydroperoxo complexes, probably DNA-Cu(I)OOH

“…The suggestion of this Cu(I)-DNA complex is based on absorption spectra, melting temperature, and circular dichroism spectra; no Cu(I)-DNA crystal structure has been resolved yet. Prütz et al [1990] expressed doubt about the Cu(I)-DNA complex theory as proposed by Michenkova and and Ivanov et al [1967], but they did not suggest an alternative. These authors agree, however, that in the case of a stable Cu(I)-DNA complex, Cu(I) is situated between the guanine and cytosine residues of the opposite DNA strands.…”

“…Because both catechol and DNA have high stability constants for copper complexes (log K ϭ 13.9 for [Cu(II)catechol] [Martell and Smith, 1989]; log K ϭ 9.3 for [Cu(I)native DNA] [Prütz et al, 1990]; no complex stability constants are available in the literature for Cu(II)DNA complexes), we investigated the role of copper complex formation prior to the final DNAdegradation experiment.…”

Identification and Quantification of a Guanine−Thymine Intrastrand Cross-Link Lesion Induced by Cu(II)/H2O2/Ascorbate

“…Among the transition metals, copper is an important structural metal in chromatin (23,24) and it can form stable complex with DNA [The association constants are 10 9 M for Cu(I)/DNA and 10 4 M for Cu(II)/DNA] (25)(26)(27). Although debate exists in the literature about the importance of the roles of copper in H 2 O 2 -induced DNA damage in vivo (28,29), most researchers believe that copper plays a significant role in H 2 O 2 -mediated DNA damage (5,23,29,30).…”

Nutritional Countermeasures Targeting Reactive Oxygen Species in Cancer: From Mechanisms to Biomarkers and Clinical Evidence

“…Among the NOX isoforms, NOX4, though predominantly localized in the ER, can also be found in the nuclei of several cell types, indicating that NOX4-dependent ROS production in the nucleus may contribute to regulation of redox-dependent transcription factors and gene expression involved in cell growth, differentiation, senescence, and apoptosis (357). Further, chelatable iron that can favor a Fenton reaction has also been found in the nucleus (280), and other metal ions such as Cu 2 + are thought to be present on the chromosomes and might also accelerate the production of ROS (285). In line, nuclear ferritin known to sequester free iron was found to ameliorate oxidative damage in embryonic avian corneal epithelial cells (51).…”