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Nitrosated peptides and polyamines as endogenous mutagens in O6-alkylguanine-DNA alkyltransferase deficient cells

B Sedgwick1

  • 1Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts, UK.

Carcinogenesis
|August 1, 1997
PubMed

Insights

Cellular metabolites like nitrosated polyamines and azaserine can damage DNA, increasing mutation rates in cells lacking O6-alkylguanine-DNA alkyltransferase. These compounds are potential endogenous mutagens, especially harmful to deficient cells.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Cells possess DNA repair mechanisms, including O6-alkylguanine-DNA alkyltransferase (AGT), to counteract DNA damage.
  • Mutations can arise from endogenous sources, with bacterial nitrosation previously suggested as a pathway for generating alkylating agents.
  • AGT-deficient mutants exhibit elevated spontaneous mutation rates, implying the existence of endogenous DNA-alkylating metabolites.

Purpose of the Study:

  • To investigate the mutagenicity of nitrosated polyamines and azaserine, a model for nitrosated peptides.
  • To determine the DNA damage mechanisms induced by these compounds.
  • To assess the role of AGT in repairing damage caused by potential endogenous mutagens.

Main Methods:

  • Utilizing Escherichia coli and Saccharomyces cerevisiae mutants deficient in O6-alkylguanine-DNA alkyltransferase (AGT) activity.
  • Treating bacterial strains with nitrosated spermidine and azaserine.
  • Analyzing DNA damage and repair pathways, including nucleotide excision repair and AGT activity.

Main Results:

  • Nitrosated polyamines and azaserine were found to be mutagenic in AGT-deficient E. coli.
  • Azaserine's mutagenicity is attributed to direct DNA methylation.
  • Nitrosated spermidine induced DNA damage requiring both nucleotide excision repair and AGT, suggesting bulky adduct formation.

Conclusions:

  • Nitrosated peptides and polyamines are identified as potential endogenous mutagens.
  • These compounds pose a particular risk to cells with deficient O6-alkylguanine-DNA alkyltransferase activity.
  • Understanding these endogenous mutagens is crucial for cellular protection and disease prevention.

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