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

Kazimierz S Kasprzak1, Wojciech Bal, Aldona A Karaczyn

  • 1Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Bldg. 538, Room 205E, Frederick, MD 21702, USA. kasprkaz@mail.ncifcrf.gov

Journal of Environmental Monitoring : JEM
|May 6, 2003
PubMed

Insights

Nickel (Ni(II)) interacts with chromatin proteins like histones and protamines, potentially causing DNA damage and altering gene expression. This molecular mechanism may contribute to nickel-induced cancer, including in offspring.

Area of Science:

  • Environmental Toxicology
  • Molecular Biology
  • Cancer Research

Background:

  • Nickel is a known carcinogen, but its precise molecular mechanisms remain under investigation.
  • Chromatin components, including DNA, histones, and protamines, are potential targets for metal-induced damage.

Purpose of the Study:

  • To investigate the molecular mechanisms of nickel-induced carcinogenesis by examining nickel's interactions with chromatin proteins.
  • To identify specific nickel-binding sites on histones and protamines and assess their functional consequences.

Main Methods:

  • Utilized synthetic peptide models to identify nickel-binding sites on histones H3, H2A, and protamine P2.
  • Assessed the effects of nickel-bound peptides on oxidative DNA base damage induced by hydrogen peroxide (H2O2).
  • Observed nickel-induced alterations in histone H2A and protamine P2 in cellular and peptide models.

Main Results:

  • Identified specific nickel-binding motifs in histone H3, H2A, and protamine P2.
  • Nickel binding to H3 and P2 motifs enhanced H2O2-mediated oxidative DNA damage.
  • Nickel-bound H2A underwent hydrolysis, forming a reactive complex capable of DNA oxidation; H2A tail cutting was observed in cells.
  • Nickel-bound protamine P2 peptides showed site-specific degradation of histidine and tyrosine residues due to nickel-induced structural changes.

Conclusions:

  • Nickel (Ni(II)) binding to chromatin proteins can lead to oxidative and structural damage to both proteins and DNA.
  • These molecular events may disrupt DNA replication fidelity and gene expression, contributing to nickel-induced carcinogenesis.
  • The findings suggest a role for nickel in paternally-mediated cancer in offspring through effects on sperm chromatin.

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