The role of chromatin damage in nickel-induced carcinogenesis. A review of recent developments.
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.
Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Bldg. 538, Room 205E, Frederick, MD 21702, USA. kasprkaz@mail.ncifcrf.gov
Kazimierz S
KS
Kasprzak
Wojciech
W
Bal
Aldona A
AA
Karaczyn
D002471:Cell Transformation, Neoplastic; D002843:Chromatin / Q000187:drug effects* / Q000502:physiology*; D018736:DNA Adducts; D004249:DNA Damage; D006657:Histones; D006801:Humans; D009532:Nickel / Q000009:adverse effects*; D011479:Protamines
D002843:Chromatin; D018736:DNA Adducts; D006657:Histones; D011479:Protamines; D009532:Nickel