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The role of chromatin damage in nickel-induced carcinogenesis. A review of recent developments

Content Provider	Royal Society of Chemistry (RSC)
Author	Bal, Wojciech Karaczyn, Aldona A. Kasprzak, Kazimierz S.
Copyright Year	2003
Abstract	Over the last years, we have been testing a hypothesis that molecular mechanisms of nickel-induced carcinogenesis include interactions of this metal with major chromatin components; DNA, histones, and protamines. Our investigations using synthetic peptide models have resulted in identification of nickel-binding sites in core histones H3 and H2A and in protamine P2. These are: the internal –Cys110–AIH– motif in histone H3; the C-terminal–E121–SHHKAKGK “tail” motif in histone H2A; and the N-terminal RTH– motif in protamine P2. Ni(II) bound to the H3 and P2 motifs enhances oxidative DNA base damage by H2O2. In contrast, Ni(II) complex with the H2A “tail” is not redox active. However, at pH 7.4, it undergoes hydrolysis yielding a new complex, Ni(II)–SHHKAKGK, reactive with H2O2 and capable of mediating DNA oxidation. The “tail” cutting of H2A has also been observed in cells cultured with Ni(II). In Ni(II) complex with the protamine P2 peptides, H2O2 causes degradation of the metal-binding His3 and the distant Tyr8 residues. This site-specificity results from a long-range structuring effect of Ni(II) on its protamine ligand. In conclusion, Ni(II) binding to some chromatin proteins in somatic and sperm cells may result in oxidative and structural damage to the proteins and DNA. These effects may alter the fidelity of DNA replication and gene expression and thus facilitate carcinogenesis, including paternally-mediated cancer in the progeny.
Starting Page	183
Ending Page	187
Page Count	5
File Format	HTM / HTML PDF
ISSN	14640325
Volume Number	5
Issue Number	2
Journal	Journal of Environmental Monitoring
DOI	10.1039/b210538c
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	SHHKAKGK Carcinogenesis Chromatin DNA Peptide Protamine Histone H3 Histone N-terminus Hydrogen peroxide Redox PH Hydrolysis 8-Oxo-2'-deoxyguanosine Ligand Spermatozoon DNA replication Gene Cancer
Content Type	Text
Resource Type	Article
Subject	Public Health, Environmental and Occupational Health Management, Monitoring, Policy and Law

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