Excision of imidazole ring-opened N7-hydroxyethylguanine from chloroethylnitrosourea-treated DNA by Escherichia coli formamidopyrimidine-DNA glycosylase.
Alkylkation of the N7 of guanine residues in DNA favours the opening of the imidazole ring, yielding a formamidopyrimidine (Fapy). This Fapy residue blocks DNA replication and is actively excised by a DNA glycosylase. We have cloned and sequenced the Escherichia coli gene responsible for synthesis of the enzyme, which has also been purified to homogeneity. It was found to have associated apurinic/apyrimidinic (AP) lyase activity, nicking DNA at AP sites. Chloroethylnitrosoureas are used in cancer chemotherapy. The lesions induced in DNA by these compounds, including N7-chloro- and hydroxyethylguanine, are excised by E. coli 3-methyladenine DNA glycosylase II, and we report that the corresponding imidazole ring-opened forms are repaired by Fapy-DNA glycosylase. Human cells have the counterpart to these enzymes, which could contribute to the repair of these lesions during chemotherapy.
Laval
J
J
Groupe Réparation des lésions radio et chimioinduites, UA147 Centre National de Recherche Scientifique, Villejuif, France.
Lopès
F
F
Madelmont
J C
JC
Godenèche
D
D
Meyniel
G
G
Habraken
Y
Y
O'Connor
T R
TR
Boiteux
S
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D003543:Cysteamine / Q000031:analogs & derivatives*; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D009699:N-Glycosyl Hydrolases / Q000494:pharmacology*; D009607:Nitrosourea Compounds / Q000494:pharmacology*
D000970:Antineoplastic Agents; D029968:Escherichia coli Proteins; D009607:Nitrosourea Compounds; C035018:N(7)-hydroxyethylguanine; D003543:Cysteamine; D006147:Guanine; D004247:DNA; C051262:N'-(2-chloroethyl)-N-(2-(methylsulfinyl)ethyl)-N'-nitrosourea; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli