Present-day cancer treatment involves DNA-damaging anticancer drugs designed to prevent replication of the cancerous cells. However, Y-family DNA polymerases found in these cells have been shown to catalyze synthesis of DNA past a variety of lesions by a process termed translesion DNA synthesis (TLS). Inhibition of human Y-family polymerases in tumors would yield more effective DNA-damaging chemotherapeutics by preventing resistance. Although not needed to maintain survival, Y-family polymerases also help microorganisms evolve under stressful conditions and can contribute to antibiotic resistance. Inhibition of microorganisms’ Y-family polymerases, such as Escherichia coli DinB, would lessen mutagenesis. Escherichia coli DinB polymerase and its mammalian ortholog, polymerase kappa (pol κ), catalyze TLS past an array of DNA lesions, most proficiently bypassing N2-dG lesions. In this study, the extension of DinB and pol κ past an N2-furfuryl-dG damaged template was assayed in the presence of varied concentrations of potential polymerase inhibitors. Under the same conditions, ligand-protein interaction was further demonstrated by thermal shift assays. Results have identified potential inhibitors of DinB and pol κ, as well as probable stimulators of DinB.

Inhibition of Y-family DNA polymerases

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.