Inhibitors of the lyase activity of DNA polymerase β

One focus of our NCDDG program is the DNA repair enzyme DNA polymerase β. This enzyme serves an important protective role by participating in the repair of lesions to DNA caused by environmental and metabolic events. However, this enzyme is also believed to help repair the damage caused by agents employed as antitumor agents, such as bleomycin and cisplatin. In this sense, transient inhibition of the enzyme concomitant with antitumor therapy might improve the effectiveness of certain DNA damaging antitumor agents. Accordingly, we have been identifying naturally occurring inhibitors of DNA polymerase β. It is now known that there are two transformations mediated by polymerase β, namely a gap-filling polymerization from which the enzyme derives its name, as well as a lyase reaction that results in excision of the deoxyribose phosphate moiety at the site of the lesion. The lyase reaction is believed to be the rate-limiting step. This presentation summarizes the status of studies of identification of inhibitors of both activities.