3,N4-ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase.
Exocyclic DNA adducts are generated in cellular DNA by various industrial pollutants such as the carcinogen vinyl chloride and by endogenous products of lipid peroxidation. The etheno derivatives of purine and pyrimidine bases 3,N4-ethenocytosine (epsilonC), 1, N6-ethenoadenine (epsilonA), N2,3-ethenoguanine, and 1, N2-ethenoguanine cause mutations. The epsilonA residues are excised by the human and the Escherichia coli 3-methyladenine-DNA glycosylases (ANPG and AlkA proteins, respectively), but the enzymes repairing epsilonC residues have not yet been described. We have identified two homologous proteins present in human cells and E. coli that remove epsilonC residues by a DNA glycosylase activity. The human enzyme is an activity of the mismatch-specific thymine-DNA glycosylase (hTDG). The bacterial enzyme is the double-stranded uracil-DNA glycosylase (dsUDG) that is the homologue of the hTDG. In addition to uracil and epsilonC-DNA glycosylase activity, the dsUDG protein repairs thymine in a G/T mismatch. The fact that epsilonC is recognized and efficiently excised by the E. coli dsUDG and hTDG proteins in vitro suggests that these enzymes may be responsible for the repair of this mutagenic lesion in vivo and be important contributors to genetic stability.
Groupe Réparation des lésions Radio-et Chimio-Induites, UMR 1772, Centre National de la Recherche Scientifique, Institut Gustave Roussy, 94805 Villejuif Cedex, France.
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M
Saparbaev
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J
Laval
D000595:Amino Acid Sequence; D001483:Base Sequence; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018736:DNA Adducts; D045647:DNA Glycosylases; D043224:Deoxyribonuclease (Pyrimidine Dimer); D004706:Endodeoxyribonucleases / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology*; D007700:Kinetics; D009153:Mutagens; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D009692:Nucleic Acid Heteroduplexes; D009838:Oligodeoxyribonucleotides; D013379:Substrate Specificity; D051981:Uracil-DNA Glycosidase
C018289:3,N(4)-ethenocytosine; D018736:DNA Adducts; D009153:Mutagens; D009692:Nucleic Acid Heteroduplexes; D009838:Oligodeoxyribonucleotides; D003596:Cytosine; D004706:Endodeoxyribonucleases; D043224:Deoxyribonuclease (Pyrimidine Dimer); D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase