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Inhibition of Ape1 nuclease activity by lead, iron, and cadmium.

  • Author(s): McNeill, Daniel R
  • Narayana, Avinash
  • Wong, Heng-Kuan
  • Wilson, David M
  • et al.

Published Web Location

https://doi.org/10.1289/ehp.7038
Abstract

Many environmental metals are co-carcinogens, eliciting their effects via inhibition of DNA repair. Apurinic/apyrimidinic (AP) endonuclease 1 (Ape1) is the major mammalian abasic endonuclease and initiates repair of this cytotoxic/mutagenic lesion by incising the DNA backbone via a Mg(2+)-dependent reaction. In this study we examined the effects of arsenite [As(III)], cadmium [Cd(II)], cobalt [Co(II)], iron [Fe(II)], nickel [Ni(II)], and lead [Pb(II)] at concentrations ranging from 0.3 to 100 microM on the incision activity of Ape1 in the presence of 1 mM MgCl(subscript)2(/subscript). Pb(II) and Fe(II) inhibited Ape1 activity at each of the concentrations tested, with an IC(subscript)50(/subscript) (half-maximal inhibitory concentration) of 0.61 and 1.0 microM, respectively. Cd(II) also inhibited Ape1 activity but only at concentrations > 10 microM. No inhibition was seen with As(III), Co(II), or Ni(II). A similar inhibition pattern was observed with the homologous Escherichia coli protein, exonuclease III, but no inhibition was seen with the structurally distinct AP endonuclease E. coli endonuclease IV, indicating a targeted effect of Pb(II), Fe(II), and Cd(II) on the Ape1-like repair enzymes. Excess nonspecific DNA did not abrogate the metal inactivation, suggesting a protein-specific effect. Notably, Cd(II), Fe(II), and Pb(II) [but not As(III), Co(II), or Ni(II)] inhibited AP endonuclease activity in whole-cell extracts but had no significant effect on single nucleotide gap filling, 5'-flap endonuclease, and nick ligation activities, supporting the idea of selective inactivation of Ape1 in cells. Our results are the first to identify a potential DNA repair enzyme target for lead and suggest a means by which these prevalent environmental metals may elicit their deleterious effects.

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