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

Lauriel F. Earley, Irina G. Minko, Plamen P. Christov, Carmelo J. Rizzo, R. Stephen Lloyd

Research output: Contribution to journalArticle

15 Scopus citations

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

ASJC Scopus subject areas

  • Toxicology

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