Studies on the mechanism of nickel‐induced heterochromatin damage; effect on specific DNA‐protein interactions

Abstract

Abstract Nickel ions selectively damage heterochromatin. Differences in the unique association of DNA and protein in heterochromatin compared to euchromatin led us to investigate a possible mechanism for this selective damage by examining the in vitro effect of nickel chloride on specific DNA‐protein interactions using a radiolabeled mouse satellite DNA sequence, which comprises the heterochromatic centromeres in mouse chromosomes. Our results indicate that nickel ions, as well as several other metal ions, inhibit specific protein binding to this DNA sequence. Inhibition of protein binding occurs at different concentrations for each metal ion but, relative to its cytotoxicity, nickel chloride seems to be a most potent inhibitor of DNA‐protein interaction. However, it should be noted that nickel ions also inhibit specific protein binding to the metallothionein promoter sequence. Magnesium ion increases the apparent affinity of proteins to the satellite DNA but not to the metallothionein promoter and decreases the inhibitory effect caused by a number of metal ions for the satellite probe. Magnesium ions have been shown to be important in heterochromatin condensation and are known to reverse some effects due to nickel ions. Because heterochromatin contains highly condensed DNA with an apparently higher density of proteins than euchromatin and because nickel interferes with the binding of these proteins, the in vitro effects of nickel ions described in this report may serve to explain the in vivo selective damage produced by nickel ions in heterochromatin. We suggest this initial damage in heterochromatin may be important in nickel carcinogenesis by causing decondensation of the heterochromatic region, thus making it susceptible to rearrangement or deletions, which are known to occur in heterochromatin regions during nickel carcinogenesis. While most of the heterochromatin regions are genetically inactive, there is evidence of gene expression in these regions in several species. Based upon current evidence, we hypothesize that the heterochromatin region in some species contains actively expressed genes involved in suppressing tumor formation and their loss induced by nickel may be an important step in tumor induction.