Nickel compounds are established human carcinogens. Their carcinogenic activity is consistently related to the ability of Ni(II) to access chromatin and cause multiple types of cellular nuclear damage via direct or indirect mechanisms. The mechanistic concepts proposed for nickel carcinogenesis include promutagenic DNA damage [1,2], epigenetic effects in chromatin [3-5], and impairment of DNA repair . The core histone octamer (formed by two copies of histones H3, H4, H2A and H2B) together with the linker histone H1, package eukaryotic DNA into repeating nucleosomal units that are folded into higher order chromatin fibres. Due to its abundance inside the cell nucleus this histone octamer is a good target for nickel binding. We focused our interest on histone H4, first of all because it has been reported that nickel(II) is a potent suppressor of histone H4 acetylation, in both yeast and mammalian cells , and this may lead to transcription errors and subsequent DNA modifications . Secondly, an anchoring binding site for nickel ion on the terminal part of this protein, specifically histidine H18, is close to sites for post-translational modifications involved in nickel toxicity. All this evidence points to the H4 tail as a candidate for Ni(II) binding on the histone octamer, and the study of its N-terminal tail as a model for metal coordination can supply useful information in the effort of unveiling the mechanisms of nickel carcinogenesis. We previously reported, by potentiometric and spectroscopic (NMR, Uv-Vis, CD) studies, about the interaction of Ni(II) with minimal models of the H4 tail: the two peptides with 6 amino acids Ac-AKRHRK-Am and with 22 amino acids Ac-SGRGKGGKGLGKGGAKRHRK VL-Am, respectively [9-11]. Here we present our recent results on the coordination ability of Ni(II) to the N-terminal tail of histone H4, the 30-amino acid peptide Ac-SGRGKGGKGLGKGGAKRH18RKVLRDNIQGITAm, achieved by the use of multidimensional NMR spectroscopy.
Involvement of histones in nickel carcinogenesis: a study of Ni(II) interactions with the 30-aa N-terminal tail of histone H4 / Zoroddu, Maria Antonietta; Peana, Massimiliano Francesco; Medici, Serenella. - In: METAL IONS IN BIOLOGY AND MEDECINE. - ISSN 1257-2535. - 9:(2006), pp. 129-132. ((Intervento presentato al convegno 9th International Symposium on Metal Ions in Biology and Medicine tenutosi a Lisbona, Portogallo nel 21-24 maggio, 2006.