Synthesis of -dA Damaged DNAs to Probe the Replication Ability of Human Translesion Polymerases.

The DNA adducts formed by the alkenylbenzene natural products, safrole (SF) and methyleugenol (MEG) are primarily attributed to their reported carcinogenic properties. Herein, we report a concise strategy to access -Ac-SF/MEG-dA phosphoramidites, which were selectively incorporated into DNA oligonucleotides by solid-phase DNA synthesis. The replication studies using human polymerases hpolκ and hpolη showed that both polymerases replicate these adducts error-free, which indicates that these polymerases do not contribute to the adduct-induced mutagenicity.

Synthesis of --isosafrole-dG-adduct Bearing DNAs and the Bypass Studies with Human TLS Polymerases κ and η.

Safrole is a natural product present in many plants and plant products, including spices and essential oils. During cellular metabolism, it converts to a highly reactive trans-isosafrole (SF) intermediate that reacts with genomic DNA and forms -SF-dG and -SF-dA DNA adducts, which are detected in the oral tissue of cancer patients with betel quid chewing history. To study the SF-induced carcinogenesis and to probe the role of low fidelity translesion synthesis (TLS) polymerases in bypassing SF adducts, herein, we report the synthesis of -SF-dG modified DNAs using phosphoramidite chemistry.

Human Translesion Synthesis Polymerases polκ and polη Perform Error-Free Replication across -dG Methyleugenol and Estragole DNA Adducts.

The secondary metabolites of polypropanoids, methyleugenol (MEG), and estragole (EG), found in many herbs and spices, are commonly used as food flavoring agents and as ingredients in cosmetics. MEG and EG have been reported to cause hepatocarcinogenicity in rodents, human livers, and lung cells. The formation of -dG and -dA DNA adducts is primarily attributed to the carcinogenicity of these compounds.