Involvement of histones in nickel carcinogenesis: a study of Ni(II) interactions with the 30-aa N-terminal tail of histone H4

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 [6].
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 [7], and this
may lead to transcription errors and subsequent DNA modifications [8]. 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.