INHIBITION OF HUMAN DNA-LIGASE-I ACTIVITY BY ZINC AND CADMIUM AND THEFIDELITY OF LIGATION

Heavy metals, including zinc (Zn) and cadmium (Cd), are potentially im portant genotoxic agents in our environment. Here we report that human DNA ligase I, the major form of the enzyme in replicative cells, is a target for Zn and Cd ions. ZnCl2 at 0.8 mM caused complete inhibition of DNA ligase I activity, whereas only 0.04 mM CdCl2 was required to achieve a similar effect. Both metals affected all three steps of the reaction, namely, the Formation of ligase-AMP intermediate, the transf er of the AMP to DNA and the ligation reaction that succeeds the forma tion of the AMP-DNA complex. Unlike F-ora-ATP and the natural protein inhibitor of DNA ligase-l, these metals may affect different domains o f the enzyme. Moreover, these metal ions did not increase the rate of misligation of F-ara-A-modified DNA or mismatched DNA substrates, but considerable misligation was observed for the T:C mispairing. These da ta support the notion of high Fidelity of the human DNA ligases and th at the major action of these metal ions on the enzyme is their inhibit ory function. (C) 1996 Wiley-Liss, Inc.