Reactivity of the C2‘-Oxidized Abasic Lesion and Its Relevance to Interactions with Type I Base Excision Repair Enzymes
Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.Chemical Research in Toxicology (Impact Factor: 3.53). 04/2006; 19(3):463-8. DOI: 10.1021/tx060001q
The C2'-oxidized abasic lesion (C2-AP) is produced in DNA that is subjected to oxidative stress. C2-AP is incised by phosphodiesterases, but is not a substrate for endonuclease III even though a Schiff base is formed (Greenberg, M. M., et al. (2004) Biochemistry 43, 15217). A chemically synthesized oligonucleotide was used to study C2-AP reactivity under alkaline conditions and with nitrogen nucleophiles chosen to mimic the lysine or N-terminal proline side chains present in the active site of Type I base excision repair enzymes. Alkaline cleavage of the C2-AP lesion produces 3'-phosphoglycoaldehyde and 3'-phosphate termini. The former is degraded further to 3'-hydroxyl groups. Cleavage at the C2-AP lesion is enhanced by small peptides, which form Schiff base intermediates with the lesion. C2-AP cleavage by Lys.Trp.Lys and Lys.Trp.Gly.Lys suggests that the inability of endonuclease III to cleave the lesion is due to the absence of appropriately positioned functional groups to take advantage of formation of the covalent intermediate. These observations leave open the possibility that the C2-AP lesion may be a substrate for other Type I repair enzymes.
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ABSTRACT: Oxidative events that target the sugar-phosphate backbone of DNA can lead to reactive fragments that interfere with DNA repair, transcription and translation by the formation of cross-links and adducts of proteins and nucleobases. Here we report the formation of several such lesions through the aerobic degradation of an independently generated C-3'-thymidinyl radical in 2'-deoxyoligonucleotides. Individual fragments were identified by independent synthesis and comparison of retention times in high-performance liquid chromatography (HPLC) and/or matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF MS) along with gel electrophoresis. The formation of this reactive intermediate in the presence of oxygen was found to produce 3'-phosphoglycolaldehyde (3'-PGA) as well as 3'-ketoenolether (3'-KEE), 3'-phosphoglycolate (3'-PG), and 5'-aldehyde terminated oligonucleotide fragments. Additionally, a significant outcome of C-3'-thymidinyl radical formation in DNA oligomers is a strand break resulting in one 3'- and two 5'-phosphate-terminated oligomers. These results suggest the involvement of several sugar derived reactive species upon C-3'-radical initiated scission of single-stranded DNA under aerobic conditions. The electrophilic nature of several of these products as well as their formation through a single oxidative event can make the presence of a C-3'-DNA radical more detrimental to the cell than products derived from more frequently occurring DNA sugar radicals.Chemical Research in Toxicology 01/2007; 19(12):1630-6. DOI:10.1021/tx060174f · 3.53 Impact Factor
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