Inhibition of O⁶-alkylguanine-DNA-alkyltransferase by metals

The activity of the DNA-repair protein O⁶-alkylguanine-DNA-alkyltransferase was found to be strongly inhibited by a number of metal ions. Cd²⁺ was the most active followed by Cu²⁺, Hg²⁺, Zn²⁺ and Ag². This inhibition is likely to result from the interaction of the metals with the cysteine-acceptor residue on the protein since the inhibition was reduced by increasing the concentration of dithiothreitol in the assay buffer. These results raise the possibility that exposure to Cd²⁺ could increase the mutagenicity and carcinogenicity of alkylating agents by retarding the rate of repair of alkylated DNA. However, other metals or metallic compounds which are known to be carcinogenic (such as compounds containing arsenic, lead, nickel or chromium) did not interfere with DNA repair by this protein.