Inhibition of human DNA ligase I activity by zinc and cadmium and the fidelity of ligation

✍ Scribed by Shu Wei Yang; Frederick F. Becker; John Y. H. Chan

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 650 KB
• Volume: 28
• Category: Article
• ISSN: 0893-6692
• DOI: 10.1002/(sici)1098-2280(1996)28:1<19::aid-em5>3.0.co;2-9

✦ Synopsis

Heavy metals, including zinc (Zn) and cadmium (Cd), are potentially important 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 CdC12 was r e quired to achieve a similar effect. Both metals affected all three steps of the reaction, namely, the formation of IigaseAMP intermediate, the transfer of the A M P to DNA and the ligation reaction that succeeds the formation of the AMP-DNA complex. Unlike F-ara-ATP and the natural protein inhibitor of DNA ligase-I, these metals may affect different domains of the enzyme. Moreover, these metal ions did not increase the rate of misligation of F-ara-Amodified DNA or mismatched DNA substrates, but considerable misligation was observed for the T:C mispairing. These data support the notion of high fidelity of the human DNA ligases and that the major action of these metal ions on the enzyme is their inhibitory function. o 1996 Wiley-Liss, tnc.