TY - JOUR
T1 - Prevention of 1-(3-Deoxycytidyl),2-(1-deoxyguanosinyl)ethane Cross-Link Formation in DNA by Rat Liver O6-Alkylguanine-DNA Alkyltransferase
AU - Ludlum, David B.
AU - Mehta, Jitendra R.
AU - Tong, William P.
PY - 1986/7/1
Y1 - 1986/7/1
N2 - Previous studies have shown that the haloethylnitrosoureas introduce the cross-link 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane into DNA. This structure is evidently formed by the following sequence of events: An initial attack of a haloethyl group on the O6 position of guanine, formation of the reactive intermediate, l,O6-ethanoguanine, and reaction of this intermediate with deoxycytidine in the opposite DNA strand. To investigate the role of O6-alkylguanine-DNA alkyltransferase in preventing the formation of this cross-link, a DNA substrate containing O6-f1uoroethylguanine has been prepared by reacting DNA with N-2-fluoroethy 1- N'- cyclohexyl - N- nitrosourea. The O6-fluoroethylguanine content of this substrate decreases when it is incubated at 37°C and pH 7.8 in the absence of repair factors because of the chemical instability of O6-fluoroethylguanine; however, this loss is accelerated by the addition of rat liver O6-alkylguanine-DNA alkyltransferase, indicating that this repair factor recognizes and repairs O6-fluoroethylguanine in DNA; furthermore, by using [chloroethyl-l4C]N-chloroethyl-N'-cyclohexyl-N-nitrosourea, it can be shown directly that the addition of rat liver O6-alkylguanine-DNA alkyltransferase prevents l-(3-deoxycytidyl),2-(l-deoxyguanosinyl)ethane formation. These studies link the presence of repair activity to the prevention of a specific cytotoxic lesion in DNA.
AB - Previous studies have shown that the haloethylnitrosoureas introduce the cross-link 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl)ethane into DNA. This structure is evidently formed by the following sequence of events: An initial attack of a haloethyl group on the O6 position of guanine, formation of the reactive intermediate, l,O6-ethanoguanine, and reaction of this intermediate with deoxycytidine in the opposite DNA strand. To investigate the role of O6-alkylguanine-DNA alkyltransferase in preventing the formation of this cross-link, a DNA substrate containing O6-f1uoroethylguanine has been prepared by reacting DNA with N-2-fluoroethy 1- N'- cyclohexyl - N- nitrosourea. The O6-fluoroethylguanine content of this substrate decreases when it is incubated at 37°C and pH 7.8 in the absence of repair factors because of the chemical instability of O6-fluoroethylguanine; however, this loss is accelerated by the addition of rat liver O6-alkylguanine-DNA alkyltransferase, indicating that this repair factor recognizes and repairs O6-fluoroethylguanine in DNA; furthermore, by using [chloroethyl-l4C]N-chloroethyl-N'-cyclohexyl-N-nitrosourea, it can be shown directly that the addition of rat liver O6-alkylguanine-DNA alkyltransferase prevents l-(3-deoxycytidyl),2-(l-deoxyguanosinyl)ethane formation. These studies link the presence of repair activity to the prevention of a specific cytotoxic lesion in DNA.
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M3 - Article
C2 - 3708569
AN - SCOPUS:0022624741
SN - 0008-5472
VL - 46
SP - 3353
EP - 3357
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -