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Inhibition of human DNA ligase I activity by zinc and cadmium and the fidelity of ligation
Author(s) -
Yang Shu Wei,
Becker Frederick F.,
Chan John Y. H.
Publication year - 1996
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/(sici)1098-2280(1996)28:1<19::aid-em5>3.0.co;2-9
Subject(s) - dna ligase , dna , enzyme , dna ligases , chemistry , ubiquitin ligase , biochemistry , dna repair , zinc , ligation , cadmium , biology , microbiology and biotechnology , ubiquitin , gene , organic chemistry
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. ZnCl 2 at 0.8 mM caused complete inhibition of DNA ligase I activity, whereas only 0.04 mM CdCl 2 was required to achieve a similar effect. Both metals affected all three steps of the reaction, namely, the formation of ligase‐AMP intermediate, the transfer of the AMP 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‐A‐modified 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. © 1996 Wiley‐Liss, Inc.