Polyvalent metal ions are highly effective in inhibiting human O6-methylguanine-DNA methyltransferase, the repair protein responsible for the removal of the promutagenic and presumably procarcinogenic adduct, O6-alkylguanine, in DNA. The sulfhydryl group-reacting metal ions (Cd2+, Zn2+, Hg2+, Pb2+) completely inhibited the reaction at concentrations of 100-500 μM while other metal ions Al3+, Fe3+) required concentrations of 1 mM or greater for significant reduction of the reaction rate. Inhibition by the former group of metals could be reversed by dithiothreitol but not by reduction of the reaction rate. Inhibition by the former group of metals could be reversed by dithiothreitol but not by EDTA, while the opposite was true for the second group. Under conditions of partial inhibition of the initial reaction rate by either Hg2+ or Al3+, the extent of reaction was not significantly affected, indicating reversible binding of these ions.
ASJC Scopus subject areas
- Cancer Research