Miscoding events during DNA synthesis past the nitration-damaged base 8-nitroguanine

Naomi Suzuki, Manabu Yasui, Nicholas E. Geacintov, Vladimir Shafirovich, Shinya Shibutani

Research output: Contribution to journalArticle

Abstract

8-Nitro-2′-deoxyguanosine (8-NO2-dG) DNA adducts are induced by the reactive nitrogen species and may be associated with the development of cancer in inflammatory tissues. To explore the miscoding potential of 8-NO2-dG adduct, an oligodeoxynucleotide containing a single 8-NO2-dG adduct was prepared by photochemical synthesis and used as a template in primer extension reactions catalyzed by mammalian DNA polymerases (pol). Primer extension reactions catalyzed by pol α or β were strongly retarded at the 8-NO2-dG lesion; a fraction of primers was extended past the lesion by incorporating preferentially dCMP, the correct base, opposite the lesion, accompanied by lesser amounts of dAMP and dGMP incorporation. In contrast, primer extension reactions catalyzed by pol η or a truncated form of pol κ (pol κΔC) readily extended past the 8-NO2-dG lesion. Pol η and κΔC snowed more broad miscoding spectra; direct incorporations of dCMP and dAMP were observed, along with lesser amounts of dGMP and dTMP incorporations and deletions. The miscoding frequencies induced by pol η and κΔC were at least 8 times higher than that of pol α or β. Miscoding frequency and specificity of 8-NO2-dG varied depending on the DNA polymerases used. These observations were supported by steady-state kinetic studies. 8-NO2-dG adduct may play an important role in initiating inflammation driven carcinogenesis.

Original languageEnglish (US)
Pages (from-to)9238-9245
Number of pages8
JournalBiochemistry
Volume44
Issue number25
DOIs
StatePublished - Jun 28 2005

ASJC Scopus subject areas

  • Biochemistry

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