Inhibitors of DNA polymerase β: Activity and mechanism

Bioassay-guided fractionation of extracts prepared from Couepia polyandra and Edgeworthia gardneri resulted in the isolation of the DNA polymerase β (pol β) inhibitors oleanolic acid (1), edgeworin (2), betulinic acid (3), and stigmasterol (4). Study of these pol β inhibitors revealed that three of them inhibited both the lyase and polymerase activities of DNA polymerase β, while stigmasterol inhibited only the lyase activity. Further investigation indicated that the four inhibitors had substantially different effects on the DNA–pol β binary complex that is believed to be an obligatory intermediate in the lyase reaction. It was found that the inhibitors potentiated the inhibitory action of the anticancer drug bleomycin in cultured A549 cells, without any influence on the expression of pol β in the cells. The results of the unscheduled DNA synthesis assay support the thesis that the potentiation of bleomycin cytotoxicity by DNA pol β inhibitors was a result of an inhibition of DNA repair synthesis.

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