DNA Polymerase ν Rapidly Bypasses O6-Methyl-dG but Not O6-[4-(3-Pyridyl)-4-oxobutyl-dG and O2-Alkyl-dTs

A. S.Prakasha Gowda, Thomas E. Spratt

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco carcinogen that forms mutagenic DNA adducts including O6-methyl-2′-deoxyguanosine (O6-Me-dG), O6-[4-(3-pyridyl)-4-oxobut-1-yl]-dG (O6-POB-dG), O2-methylthymidine (O2-Me-dT), and O2-POB-dT. We evaluated the ability of human DNA polymerase ν to bypass this damage to evaluate the structural constraints on substrates for pol ν and to evaluate if there is kinetic evidence suggesting the in vivo activity of pol ν on tobacco-induced DNA damage. Presteady-state kinetic analysis has indicated that O6-Me-dG is a good substrate for pol ν, while O6-POB-dG and the O2-alkyl-dT adducts are poor substrates for pol ν. The reactivity with O6-Me-dG is high with a preference for dCTP > dGTP > dATP > dTTP. The catalytic activity of pol ν toward O6-Me-dG is high and can potentially be involved in its bypass in vivo. In contrast, pol ν is unlikely to bypass O6-POB-dG or the O2-alkyl-dTs in vivo.

Original languageEnglish (US)
Pages (from-to)1894-1900
Number of pages7
JournalChemical research in toxicology
Volume29
Issue number11
DOIs
StatePublished - Nov 21 2016

All Science Journal Classification (ASJC) codes

  • Toxicology

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