Mutagenic spectra arising from replication bypass of the 2,6-diamino-4-hydroxy-N(5)-methyl formamidopyrimidine adduct in primate cells.

Earley LF, Minko IG, Christov PP, Rizzo CJ, Lloyd RS
Chem Res Toxicol. 2013 26 (7): 1108-14

PMID: 23763662 · PMCID: PMC3830661 · DOI:10.1021/tx4001495

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 O(6)-Me-dG and O(4)-Me-dT, the MeFapy-dG adduct likely contributes to mutagenic events following chemotherapeutic treatments.

MeSH Terms (9)

Animals Base Sequence Chlorocebus aethiops COS Cells DNA Adducts DNA Replication Mutagenesis Mutagenicity Tests Pyrimidines

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