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A more recent version of this article appeared on September 27, 2002
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M206027200v1
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Papers In Press, published online ahead of print July 26, 2002
J. Biol. Chem, 10.1074/jbc.M206027200
Submitted on June 18, 2002
Revised on July 24, 2002
Accepted on July 25, 2002

Human DNA polymerase kappa bypasses and extends beyond thymine glycols during translesion synthesis in vitro, preferentially incorporating correct nucleotides

Paula L. Fischhaber, Valerie L. Gerlach, William J. Feaver, Zafer Hatahet, Susan S. Wallace, and Errol C. Friedberg

Pathology Dept., University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9072

Corresponding Author: friedberg.errol{at}pathology.swmed.edu

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. 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 amongst 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 non-mutagenic and mutagenic bypass of oxidative damage.


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