Novel Approaches for Modulating dUTPase and Uracil-DNA Glycosylase: Potential Uses for Cancer and Viral Chemotherapy

Uracil residues arise in DNA through the misincorporation of deoxyuridine triphosphate (dUTP) by DNA polymerizing enzymes (DNA polymerases and reverse transcriptases) and from the deamination of deoxycytidine residues in DNA. The detrimental effects of uracil residues in DNA are well established. However, recent studies have demonstrated, that the regulated formation and excision of uracil residues from DNA is important in creating immunoglobulin dirversity and that it may also function as a host protection mechanism against certain viral infections. The key enzymes, which function in tandem to prevent the incorporation and retention of uracil residues in DNA, are deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and uracil-DNA glycosylase, respectively. While it has been suggested that either dUTPase or UNG could be targets for the development of specific chemotherapeutic agents, none have been developed that are effective in vivo. This review focuses on summarizing recent studies examining the role(s) that dUTPase and UNG have in normal cellular metabolism and virus replication and on studies directed to modulating these enzymes using small interfering RNA (siRNA) and protein transduction technologies.