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Originally published In Press as doi:10.1074/jbc.M200316200 on February 11, 2002

J. Biol. Chem., Vol. 277, Issue 17, 14589-14597, April 26, 2002
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Effects of a Guanine-derived Formamidopyrimidine Lesion on DNA Replication
TRANSLESION DNA SYNTHESIS, NUCLEOTIDE INSERTION, AND EXTENSION KINETICS*

Kenjiro Asagoshi, Hiroaki Terato, Yoshihiko Ohyama, and Hiroshi IdeDagger

From the Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan

2,6-Diamino-4-hydroxy-5-formamidopyrimidine derived from guanine (FapyG) is a major DNA lesion formed by reactive oxygen species. In this study, a defined oligonucleotide template containing a 5-N-methylated analog of FapyG (mFapyG) was prepared, and its effect on DNA replication was quantitatively assessed in vitro. The results were further compared with those obtained for 7,8-dihydro-8-oxoguanine and an apurinic/apyrimidinic site embedded in the same sequence context. mFapyG constituted a fairly strong but not absolute block to DNA synthesis catalyzed by Escherichia coli DNA polymerase I Klenow fragment with and without an associated 3'-5' exonuclease activity, thereby permitting translesion synthesis with a limited efficiency. The efficiency of translesion synthesis was G > 7,8-dihydro-8-oxoguanine > mFapyG > apurinic/apyrimidinic site. Analysis of the nucleotide insertion (fins = Vmax/Km for insertion) and extension (fext = Vmax/Km for extension) efficiencies for mFapyG revealed that the extension step constituted a major kinetic barrier to DNA synthesis. When mFapyG was bypassed, dCMP, a cognate nucleotide, was preferentially inserted opposite the lesion (dCMP (relative fins = 1) dTMP (2.4 × 10-4) approx  dAMP (8.1 × 10-5) > dGMP (4.5 × 10-7)), and the primer terminus containing a mFapyG:C pair was most efficiently extended (mFapyG:C (relative fext = 1) > mFapyG:T (4.6 × 10-3) mFapyG:A and mFapyG:G (extension not observed)). Thus, mFapyG is a potentially lethal but not premutagenic lesion.

* This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to H. I.) and by a research fellowship for young scientists from the Japan Society for the Promotion of Science (to K. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel. and Fax: 81-824-24-7457; E-mail: ideh@hiroshima-u.ac.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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