N(2)-(1-Carboxyethyl)deoxyguanosine, a nonenzymatic glycation adduct of DNA, induces single-strand breaks and increases mutation frequencies.
N(2)-(1-Carboxyethyl)deoxyguanosine (CEdG) is a major nonenzymatic glycation product of DNA. The effect of CEdG modification, which was specifically prepared by incubation with dihydroxyacetone, on plasmid DNA topology was evaluated by gel electrophoresis. A time-dependent decrease of supercoiled plasmid-DNA was observed in parallel to the increase of CEdG adducts; the half-life time of the supercoiled plasmid-DNA was estimated to be approximately 16-18 h. CEdG-modified plasmid DNA showed a 25-fold reduced transformation efficiency. When modified DNA was used to transform Escherichia coli cells, a 6-fold increase in mutation frequency was determined by measuring loss of alpha-complementation. For the mutator strain BMH71-18mutS, an 8-fold increase in mutation frequency was observed. Although the exact mechanism of DNA damage is unclear, the occurrence of spontaneous depurination is likely. These findings suggest that a defined DNA glycation reaction can lead to DNA damage in vivo.
Pischetsrieder
M
M
Institut für Pharmazie und Lebensmittelchemie der Universität Erlangen, Erlangen, Germany.
Seidel
W
W
Münch
G
G
Schinzel
R
R
D018736:DNA Adducts / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000737:chemistry; D006207:Half-Life; D009154:Mutation; D010084:Oxidation-Reduction; D010957:Plasmids / Q000737:chemistry
D018736:DNA Adducts; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D005947:Glucose