Structure and potential mutagenicity of new hydantoin products from guanosine and 8-oxo-7,8-dihydroguanine oxidation by transition metals.
In vitro work in this laboratory has identified new DNA lesions resulting from further oxidation of a common biomarker of oxidative damage, 8-oxo-7,8-dihydroguanine (OG). The major product of oxidation of OG in a nucleoside, nucleotide, or single-stranded oligodeoxynucleotide using metal ions that act as one-electron oxidants is the new nucleoside derivative spiroiminodihydantoin (Sp). In duplex DNA an equilibrating mixture of two isomeric products, guanidinohydantoin (Gh) and iminoallantoin (Ia), is produced. These products are also formed by the overall four-electron oxidation of guanosine by photochemical processes involving O(2). DNA template strands containing either Sp or Gh/Ia generally acted as a block to DNA synthesis with the Klenow exo(-) fragment of pol I. However, when nucleotide insertion did occur opposite the lesions, only 2'-deoxyadenosine 5-triphosphate and 2'-deoxyguanine 5-triphosphate were used for primer extension. The Escherichia coli DNA repair enzyme Fpg was able to remove the Sp and Gh/Ia lesions from duplex DNA substrates, although the efficiency was depended on the base opposite the lesion.
Burrows
Cynthia J
CJ
Department of Chemistry, University of Utah, 315 S. 1400 East, Salt Lake City, UT 84112-0850, USA. burrows@chem.utah.edu
Muller
James G
JG
Kornyushyna
Olga
O
Luo
Wenchen
W
Duarte
Victor
V
Leipold
Michael D
MD
David
Sheila S
SS
D015415:Biomarkers / Q000032:analysis; D004249:DNA Damage; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000494:pharmacology; D006147:Guanine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D006151:Guanosine / Q000009:adverse effects* / Q000031:analogs & derivatives; D006801:Humans; D006827:Hydantoins / Q000009:adverse effects* / Q000737:chemistry; D009152:Mutagenicity Tests; D010083:Oxidants, Photochemical / Q000009:adverse effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010126:Ozone / Q000009:adverse effects; D010777:Photochemistry
D015415:Biomarkers; D006827:Hydantoins; D010083:Oxidants, Photochemical; D006151:Guanosine; C024829:8-hydroxyguanine; D006147:Guanine; D010126:Ozone; D004259:DNA-Directed DNA Polymerase