The preservation of genomic integrity is essential for cellular function. Damage caused by radiation, radicals and other reactive chemical species can corrupt the information content of genomes by changing the chemical identities of the DNA bases or causing strand scission. A newly discovered pathway for nucleic acids damage is under investigation in our laboratory that involves cleavage of the DNA backbone by amino acid peroxides. While oxidative damage involving DNA and proteins has been considered separately, the interrelationship between the two types of damage events is unexplored. Using model peptides and synthetic peptidoconjugates, we are modeling reactions occurring between oxidized protein residues and DNA both in vitro and within human cells. Our studies have revealed that a subset of protein residues can form cyclic peroxides and promote strand breakage when presented to DNA. The observation of amino acid promoted DNA damage indicates that crossreactions within protein/DNA complexes should be considered as a significant cause of the toxicity of reactive oxygen species.
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