Cu(II)–histones interaction related to toxicity-carcinogenesis

• We summarize the work done towards elucidation of Cu metal binding sites in histones.
• Efficient Cu(II) binding is proposed in almost all the peptide sequences studied.
• Metal coordination impact on both genotoxic and epigenetic mechanisms leading to mutations is discussed.

In this review, we summarize the research work performed in the last years to elucidate the Cu(II) induced toxicity-carcinogenesis mechanisms based on studies of Cu(II) interactions with histone model peptides the most abundant protein part of cell nucleus. Oligopeptide models of histones, synthesized and used in most cases, helped us to determine stoichiometry, binding sites, conformations adopted and DNA damage caused by the metal. They are all reviewed and discussed, in an attempt to better understand the mechanisms of carcinogenesis caused by Cu(II) ions. The metal–histones interaction affecting both DNA oxidative damage pathways and possibly the cause of epigenetic effects have also been considered. Strong Cu(II) binding especially at physiological pH values provided by a 3N (Nim, 2N−} donor set could promote genotoxicity (DNA single/double strand scission) while induction of epigenetic changes might be the result of severe histone conformational changes affecting post-translational machinery (“histone code”).