DNA-polyamine adducts from purine oxidation

All organisms owe their development, growth, and survival to the flawless interpretation of the genome. Oxidative damage to genomic DNA may impede or perturb the flow of information within the cell, ultimately leading to deranged cellular metabolism, and possibly cell death. At the molecular level, DNA is especially susceptible to oxidation at guanine. Reactive oxygen species are a considerable threat to guanine since cellular oxidizers like hydroxyl radical, superoxide, and singlet oxygen modify guanine by 2 e- oxidation to 8-oxoguanine (OG). OG is itself easily oxidized to an extremely electrophilic quinonoid nucleobase, termed OGOX. Proximal biological nucleophiles, as well as water, readily add to OG OX and provide covalent guanine adducts. Polyamines are logical reaction partners for adduction to oxidized guanine since the polycationic skeleton, as well as their millimolar cellular concentrations, ensure reliable access to the nucleic acids. Indeed, polyamines react efficiently with OG, and to a lesser extent guanine, following oxidation (by Ir(IV) with OG, or 1O2 with G) leading to guanine-polyamine adducts, which hydrolyze to deoxyribosylurea lesions. Rearrangement or fragmentation of the adducts is expected to be a severe impediment to DNA's fitness with respect to information transfer (mRNA production) and DNA replication. Oxidation of 8-oxoadenine also provides DNA polyamine adducts, although their formation and structural features are more elusive than the analogous OG adducts.; A second area of research is presented that focuses on the employment of in vitro selection (SELEX) to identify privileged adenine residues (within a library of RNA randomers) that engage in metal-mediated imine formation with salicylaldehyde. Progress towards this goal was achieved in the form of a novel salicyladimine ligand, composed of an adenine nucleotide and salicylaldehyde. Although the ligand was very sensitive to hydrolysis, analyses of the ligand bound to Ni(II) suggested a square-planar complex in which solvent, or a free adenine occupy the fourth position of the square plane. The results are promising and future directions in this area are addressed.