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Pawe Jaoszyski^1,a,*, Eiji Ohashi², Haruo Ohmori² and Susumu Nishimura¹

¹ Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
² Institute for Virus Research, Kyoto University, Shogoin-Kawaracho 53, Sakyo-ku, Kyoto, 606-8507, Japan

Using fragments of human c-Ha-ras and mouse Ha-ras1 genes containing 8-hydroxyguanine (8-OH-G) in hypermutagenic codon 12, we analyzed the kinetics of DNA synthesis catalyzed by human Pol. This translesion DNA polymerase, belonging to the Y-family, was found to be moderately inhibited by the presence of 8-OH-G on either mouse or human templates. From our previous results, inhibition of various polymerases by 8-OH-G increases in the following order: Pol < Pol < Polß < Pol, showing that major replicative and repair polymerases are more sensitive to this lesion than enzymes belonging to the Y-family. In the direct mutagenesis experiments, Pol was found to be more mutagenic than Pol studied previously: it inserted dAMP more efficiently than dCMP opposite 8-OH-G. Pol was also able to cause indirect mispair (‘action-at-a-distance’ mutagenesis), this effect being more distinct on mouse templates. Two adjacent 8-OH-G residues in codon 12 inhibited Pol moderately and induced misincorporation of dAMP. However, this effect was not comparable to the strong relaxation of the enzyme specificity, observed previously in the case of Pol. Pol catalyzed incorporation (and misincorporation of dAMP) much more efficiently on mouse templates, human DNA fragments being distinctly worse substrates. Interestingly, in direct mutagenesis systems, the preference for dAMP over dCMP was nearly the same on mouse and human templates.

^aPresent address: Institute of Human Genetics, Polish Academy of Sciences, Strzeszyñska 32, 60-479 Pozna, Poland

^* Correspondence: E-mail: japawel{at}man.poznan.pl

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