Mutagenic spectra arising from replication bypass of the 2,6-diamino-4-hydroxy-N5-methyl formamidopyrimidine adduct in primate cells

Lauriel F. Earley, Irina Minko, Plamen P. Christov, Carmelo J. Rizzo, Robert (Stephen) Lloyd

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Abstract

DNA exposures to electrophilic methylating agents that are commonly used during chemotherapeutic treatments cause diverse chemical modifications of nucleobases, with reaction at N7-dG being the most abundant. Although this base modification frequently results in destabilization of the glycosyl bond and spontaneous depurination, the adduct can react with hydroxide ion to yield a stable, ring-opened MeFapy-dG, and this lesion has been reported to persist in animal tissues. Results from prior in vitro replication bypass investigations of the MeFapy-dG adduct had revealed complex spectra of replication errors that differed depending on the identity of DNA polymerase and the local sequence context. In this study, a series of nine site-specifically modified MeFapy-dG-containing oligodeoxynucleotides were engineered into a shuttle vector and subjected to replication in primate cells. In all nine sequence contexts examined, MeFapy-dG was shown to be associated with a strong mutator phenotype, predominantly causing base substitutions, with G to T transversions being most common. Single and dinucleotide deletions were also found in a subset of the sequence contexts. Interestingly, single-nucleotide deletions occurred at not only the adducted site, but also one nucleotide downstream of the adduct. Standard models for primer-template misalignment could account for some but not all mutations observed. These data demonstrate that in addition to mutagenesis predicted from replication of DNAs containing O6-Me-dG and O 4-Me-dT, the MeFapy-dG adduct likely contributes to mutagenic events following chemotherapeutic treatments.

Original languageEnglish (US)
Pages (from-to)1108-1114
Number of pages7
JournalChemical Research in Toxicology
Volume26
Issue number7
DOIs
StatePublished - Jul 15 2013

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Primates
Nucleotides
Genetic Vectors
Mutagenesis
Oligodeoxyribonucleotides
DNA
Chemical modification
DNA-Directed DNA Polymerase
DNA Replication
Animals
Substitution reactions
N6-(2-deoxypentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine
Tissue
Phenotype
Mutation

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

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Mutagenic spectra arising from replication bypass of the 2,6-diamino-4-hydroxy-N5-methyl formamidopyrimidine adduct in primate cells. / Earley, Lauriel F.; Minko, Irina; Christov, Plamen P.; Rizzo, Carmelo J.; Lloyd, Robert (Stephen).

In: Chemical Research in Toxicology, Vol. 26, No. 7, 15.07.2013, p. 1108-1114.

Research output: Contribution to journalArticle

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