6-Nitrochrysene (6-NC) is a potent mutagen in bacteria. It is an exceptionally potent carcinogen in newborn mice, and it induces mammary carcinoma in rats. The genotoxicity of 6-NC is derived from its ability to generate DNA adducts such as N-(2'-deoxyadenosine-8-yl)-6-aminochrysene, N-(dA-8-yl)-6-AC which was shown to be repaired inefficiently by the nucleotide excision repair system in humans. To investigate its replication properties, we have synthesized N-(dA-8-yl)-6-AC adducted nucleoside using palladium cross-coupling chemistry. The adducted nucleoside was converted to its corresponding protected 3’-phosphoramidite, which was used to synthesize site-specific 12 mer and 15-mer oligonucleotides. To investigate the mutagenicity and translesion synthesis (TLS) efficiency of N-(dA-8-yl)-6-AC, the modified oligonucleotides were inserted into a plasmid to construct site-specifically modified vectors using recombinant DNA technology. These vectors were replicated in E. Coli and human embryonic kidney 293T (HEK293T) cells. Preliminary results in E. Coli showed that viability of the lesion is ~66% relative to control, and the major type of mutation induced by N-(dA-8-yl)-6-AC is A→ G (2%) transitions and A→T transversions at the base 5' to the lesion site as well as other semi targeted mutations (3%). In HEK293T cells, N-(dA-8-yl)-6-AC is a strong replication block, but significant TLS also occurred. Mutational analyses in HEK293T cells are in progress.

Mutagenicity of the C8-adenine adduct derived from the environmental carcinogen 6-nitrochrysene in Escherichia coli and human cells

2019 Fall National Meeting

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