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Biological and Pharmaceutical Bulletin
Vol. 31 (2008) No. 11 P 2007-2011

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http://doi.org/10.1248/bpb.31.2007

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Nickel compounds have toxic and carcinogenic effects. Several cellular targets have been identified and the toxicity is thought to be mediated by genetic and epigenetic factors. Gene expression from chromatin is regulated by posttranslational histone modifications, ATP-dependent chromatin remodeling, and the incorporation of histone variants. Nickel compounds decrease acetylation levels of all four histones and increase ubiquitylation of H2A and H2B and dimethylation of H3 lysine 9. Less attention has been focused on histone variants in nickel toxicity. Here we demonstrate that a null mutation of H2A.Z (HTZ1 in Saccharomyces cerevisiae), a variant of H2A, decreases the sensitivity to soluble nickel compounds. In addition, we show that a mutation in the acetylatable residues in Htz1p does not alter the sensitivity to nickel compounds. Furthermore, sensitivity to nickel compounds of the null mutant of SWR1 encoding the catalytic subunit of the ATP-dependent chromatin remodeling complex that specifically loads Htz1p into chromatin, was identical to that of the htz1 mutant. Taken together, these results reveal that the incorporation into chromatin, but not acetylation, of Htz1p is important to the toxicity of nickel compounds.

Copyright © 2008 The Pharmaceutical Society of Japan

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