Involvement of DNA Conformational Change Induced by Rearrangement of Copper-coordination Geometry in Oxidative DNA Damages Caused by Copper and Dopamine

Abstract

Oxidative DNA damages involve reductionoxidation reactions between certain metals and compounds, and result in genetic abnormalities leading to diseases including cancer and neurodegenerative disorders. Here, we report that DNA damages mediated by combination of a neurotransmitter dopamine and copper accompany a unique DNA conformational change. Copper(II) [Cu(II)] was shown as bound to consecutive guanines (G-G) of DNA, by demonstrating the G-G selective inhibition of restriction enzymes. When dopamine was added to calf thymus DNA in the presence of Cu(II), DNA guanines were oxidized. UV and 1 H NMR analyses suggested that dopamine was oxidized to the quinone form in the presence of Cu(II). The circular dichroism experiments showed DNA spectral changes under the conditions of oxidative DNA damage, indicating a conformational change of the DNA strand by dopamine and copper. The DNA conformational change was suppressed by adding a Cu(I)-specific chelator bathocuproine. Therefore, the conformational change can be explained by a rearrangement of the copper-coordination geometry in DNA through Cu(II) reduction to Cu(I). Thus, changes in DNA conformation could be involved in metal-mediated genotoxicity as well as oxidative damage but via different mechanism.

Combined Effects of Manganese, Iron, Copper, and Dopamine on Oxidative DNA Damage

“…Cu(II) is closely located to DNA, and its reduced form Cu(I) tightly binds to DNA and introduces a conformational change. 24) The bound Cu(I) anchors the H 2 O 2 that attacks DNA by forming a DNA-Cu(I)-OOH complex. 16) In contrast, Fe(III)-NTA provides hydroxyl radicals far from DNA.…”

Different Mechanisms Between Copper and Iron in Catecholamines-Mediated Oxidative DNA Damage and Disruption of Gene Expression In Vitro

“…This Cu reduction and subsequent ROS production together with dissolved oxygen induce oxidative damage and conformational changes in DNA strand, as detected by CD measurement. DNA conformational changes are induced by rearrangement of the copper-coordination geometry in DNA through Cu(II) reduction to Cu(I) (Ando et al 2009). In contrast to Cu, iron yielded no detectable changes in the CD spectra of treated DNA.…”

“…Copper is present in the nucleus and plays a role in maintaining higher order DNA structure (Bryan et al 1981;Dijkwel and Wenink 1986). We reported previously that Cu(II) selectively binds to consecutive guanine sequences of purified DNA and that DNA conformation is altered by the combination of dopamine and transition metals such as copper (Ando et al 2009). …”

“…Although catechols are critical in Cu-mediated DNA damage, the effect of the ring side chain with the amino group is unclear. Several groups have reported that dopamine induces oxidative DNA damage (Oikawa et al 2006;Ando et al 2009). Dopamine may be involved in the pathogenesis of a neurodegenerative disorder, Parkinson's disease, which shows the selective degeneration of substantia nigra pars compacta comprising dopaminergic neurons (Hastings et al 1996;Oikawa et al 2006;Linert and Jameson 2000).…”

A computational study of the interaction between dopamine and DNA/RNA nucleosides

“…In a different study, it was found that dopamine quenches excited singlet and triplet states of riboflavin [15,16]. Furthermore, dopamine may break a DNA strand in the presence of Cu ion [14,17].…”