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


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 ? to bypass this damage to evaluate the structural constraints on substrates for pol ? and to evaluate if there is kinetic evidence suggesting the in vivo activity of pol ? on tobacco-induced DNA damage. Presteady-state kinetic analysis has indicated that O6-Me-dG is a good substrate for pol ?, while O6-POB-dG and the O2-alkyl-dT adducts are poor substrates for pol ?. The reactivity with O6-Me-dG is high with a preference for dCTP > dGTP > dATP > dTTP. The catalytic activity of pol ? toward O6-Me-dG is high and can potentially be involved in its bypass in vivo. In contrast, pol ? is unlikely to bypass O6-POB-dG or the O2-alkyl-dTs in vivo.

PROVIDER: S-EPMC5673091 | BioStudies |

REPOSITORIES: biostudies

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