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Originally published In Press as doi:10.1074/jbc.M202021200 on March 27, 2002

J. Biol. Chem., Vol. 277, Issue 22, 19633-19638, May 31, 2002
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Low Fidelity DNA Synthesis by a Y Family DNA Polymerase Due to Misalignment in the Active Site*

Robert J. KokoskaDagger , Katarzyna BebenekDagger , François Boudsocq§, Roger Woodgate§, and Thomas A. KunkelDagger ||

From the Dagger  Laboratory of Molecular Genetics and  Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709 and § Section on DNA Replication, Repair, and Mutagenesis, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Sulfolobus solfataricus DNA polymerase IV (Dpo4) is a member of the Y family of DNA polymerases whose crystal structure has recently been solved. As a model for other evolutionarily conserved Y family members that perform translesion DNA synthesis and have low fidelity, we describe here the base substitution and frameshift fidelity of DNA synthesis by Dpo4. Dpo4 generates all 12 base-base mismatches at high rates, 11 of which are similar to those of its human homolog, DNA polymerase kappa . This result is consistent with the Dpo4 structure, implying lower geometric selection for correct base pairs. Surprisingly, Dpo4 generates C·dCMP mismatches at an unusually high average rate and preferentially at cytosine flanked by 5'-template guanine. Dpo4 also has very low frameshift fidelity and frequently generates deletions of even noniterated nucleotides, especially cytosine flanked by a 5'-template guanine. Both unusual features of error specificity suggest that Dpo4 can incorporate dNTP precursors when two template nucleotides are present in the active site binding pocket. These results have implications for mutagenesis resulting from DNA synthesis by Y family polymerases.

* 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.

|| To whom correspondence should be addressed. Tel.: 919-541-2644; Fax: 919-541-7613; E-mail: kunkel@niehs.nih.gov.

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