Competitive inhibition of uracil DNA glycosylase by a modified nucleotide whose triphosphate is a substrate for DNA polymerase

Haidong Huang, James T. Stivers, Marc M. Greenberg

Research output: Contribution to journalArticle

Abstract

Base excision repair (BER) enzymes are attractive targets for antiviral and anticancer agents. A number of nucleotides and nucleotide analogues are potent competitive inhibitors of BER glycosylases when they are incorporated into synthetic oligonucleotides. However, these molecules often are not substrates for DNA polymerases, which limits their utility in cells and as potential therapeutic agents. 1B-Cyano-2B-deoxyuridine (CNdU) is a nanomolar competitive inhibitor of uracil DNA glycosylase. In addition, the respective nucleotide triphosphate is accepted as a substrate by the Klenow fragment (exo -) of DNA polymerase I from E. coli. This is the first competitive inhibitor of UDG that is incorporated into DNA by Klenow exo -, a model replicative polymerase. 1B-Cyano-2B-deoxyuridine (CNdU) and related molecules may prove useful as a new family of therapeutic or experimental agents that target DNA repair by using the cells' polymerase(s) to incorporate them into DNA. A potential benefit of such a mechanism is that multiple incorporations can occur for longer DNA molecules leading to amplification of the inhibitory effect beyond that seen here with short DNA duplexes.

Original languageEnglish (US)
Pages (from-to)1344-1345
Number of pages2
JournalJournal of the American Chemical Society
Volume131
Issue number4
DOIs
StatePublished - Feb 4 2009

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint Dive into the research topics of 'Competitive inhibition of uracil DNA glycosylase by a modified nucleotide whose triphosphate is a substrate for DNA polymerase'. Together they form a unique fingerprint.

Cite this