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Originally published In Press as doi:10.1074/jbc.M206027200 on July 26, 2002

J. Biol. Chem., Vol. 277, Issue 40, 37604-37611, October 4, 2002
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Human DNA Polymerase kappa  Bypasses and Extends beyond Thymine Glycols during Translesion Synthesis in Vitro, Preferentially Incorporating Correct Nucleotides*

Paula L. FischhaberDagger §, Valerie L. GerlachDagger ||, William J. FeaverDagger **, Zafer HatahetDagger Dagger , Susan S. Wallace§§, and Errol C. FriedbergDagger ¶¶

From the Dagger  Laboratory of Molecular Pathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072 and the §§ Department of Microbiology and Molecular Genetics, Markey Center for Molecular Genetics, University of Vermont, Burlington, Vermont 05405-0068

Human polymerase kappa  (polkappa ), the product of the human POLK (DINB1) gene, is a member of the Y superfamily of DNA polymerases that support replicative bypass of chemically modified DNA bases (Ohmori, H., Friedberg, E. C., Fuchs, R. P., Goodman, M. F., Hanaoka, F., Hinkle, D., Kunkel, T. A., Lawrence, C. W., Livneh, Z., Nohmi, T., Prakash, L., Prakash, S., Todo, T., Walker, G. C., Wang, Z., and Woodgate, R. (2001) Mol. Cell 8, 7-8; Gerlach, V. L., Aravind, L., Gotway, G., Schultz, R. A., Koonin, E. V., and Friedberg, E. C. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 11922-11927). Polkappa is shown here to bypass 5,6-dihydro-5,6-dihydroxythymine (thymine glycol) generated in two different DNA substrate preparations. Polkappa inserts the correct base adenine opposite thymine glycol in preference to the other three bases. Additionally, the enzyme correctly extends beyond the site of the thymine glycol lesion when presented with adenine opposite thymine glycol at the primer terminus. However, steady state kinetic analysis of nucleotides incorporated opposite thymine glycol demonstrates different misincorporation rates for guanine with each of the two DNA substrates. The two substrates differ only in the relative proportions of thymine glycol stereoisomers, suggesting that polkappa distinguishes among stereoisomers and exhibits reduced discrimination between purines when incorporating a base opposite a 5R thymine glycol stereoisomer. When extending beyond the site of the lesion, the misincorporation rate of polkappa for each of the three incorrect nucleotides (adenine, guanine, and thymine) is dramatically increased. Our findings suggest a role for polkappa in both nonmutagenic and mutagenic bypass of oxidative damage.

* This work was supported by United States Public Health Service Grants CA4424717 (to E. C. F.) and CA52040 (to S. S. W.).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.

§ Supported by NCI, National Institutes of Health, Postdoctoral Fellowship CA83314.

Present address: CuraGen Corp., 322 E. Main St., Branford, CT 06405.

|| Supported by NCI, National Institutes of Health, Postdoctoral Fellowship CA75733.

** Present address: Molecular Staging, 300 George, New Haven, CT 06511.

Dagger Dagger Present address: Dept. of Biochemistry, University of Texas Health Center at Tyler, Tyler, TX 75708.

¶¶ To whom correspondence should be addressed. Tel.: 214-648-4020; Fax: 214-648-4067; E-mail: friedberg.errol@pathology.swmed.edu.

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


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