Human exposure to toxic metals including nickel and toxic oxides including SO(x) and NO(x) results in damage to genetic material. These environmental toxins are encountered occupationally in the mining, steel and welding industries as well as being constituents of particulate and gaseous air pollution and additives to food and wine.
This research aims to investigate the role of nickel and related metal ions in mediating oxidative DNA damage using biologically relevant ligands, such as peptides, and biologically relevant oxidants including dioxygen, sulfite, and peroxynitrite. Four areas will be examined. (1) Nickel peptides activating O(2) will be explored. Certain nickel(II) peptide complexes have been found to react with molecular oxygen and cause oxidative damage to DNA. The role of this mechanism in carcinogenesis nd the potential application to protein-nucleic acid interactions via efficient design of the peptide will be examined including ligand radical formation as a key element to O(2) reactivity of the peptide. (2) The chemistry of sulfate and sulfite radicals with nucleic acids will be studied. These species may be generated from SO(3)(2-) in the presence of transition metal ions and O(2). Importantly, the transition metals to be studied will be cobalt, nickel and copper complexes of biologically relevant ligands, namely peptides. These studies will provide insight into the mechanism of sulfite toxicity in conjunction with transition metals. (3) The chemistry of NO and peroxynitrite with nickel peptides will be studied. Nickel(II)-catalyzed decomposition of HO(2)NO should lead to NO(2), a species capable of reaction with nucleobases and proteins. (4) Nickel-mediated chemistry of DNA-binding protein fragments will be explored at the same time as the mechanistic studies listed above. Such systems might include oligopeptides such as SPXY repeats present in histones, distamycin mimics such PRGRP, or RNA-binding peptides. The immediate goal is to study processes related to in vivo DNA damage mediated by nickel.
| Van Horn, J David; Bulaj, Grzegorz; Goldenberg, David P et al. (2003) The Cys-Xaa-His metal-binding motif: [N] versus [S] coordination and nickel-mediated formation of cysteinyl sulfinic acid. J Biol Inorg Chem 8:601-10 |
| Stemmler, A J; Burrows, C J (2001) Guanine versus deoxyribose damage in DNA oxidation mediated by vanadium(IV) and vanadium(V) complexes. J Biol Inorg Chem 6:100-6 |
