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Originally published In Press as doi:10.1074/jbc.M102694200 on June 11, 2001

J. Biol. Chem., Vol. 276, Issue 33, 30615-30622, August 17, 2001
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Human DNA Polymerase iota  Promiscuous Mismatch Extension*

Alexandra VaismanDagger , Agnès TissierDagger §, Ekaterina G. FrankDagger , Myron F. Goodman, and Roger WoodgateDagger ||

From the Dagger  Section on DNA Replication, Repair, and Mutagenesis, NICHD, National Institutes of Health, Bethesda, Maryland 20892-2725, and  Departments of Biological Sciences and Chemistry, Hedco Molecular Biology Laboratories, University of Southern California, University Park, Los Angeles, California 90089-1340

Human DNA polymerase iota  is a low-fidelity template copier that preferentially catalyzes the incorporation of the wobble base G, rather than the Watson-Crick base A, opposite template T (Tissier, A., McDonald, J. P., Frank, E. G., and Woodgate, R. (2000) Genes Dev. 14, 1642-1650; Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S., and Prakash, L. (2000) Nature 406, 1015-1019; Zhang, Y., Yuan, F., Wu, X., and Wang, Z. (2000) Mol. Cell. Biol. 20, 7099-7108). Here, we report on its ability to extend all 12 possible mispairs and 4 correct pairs in different sequence contexts. Extension from both matched and mismatched primer termini is generally most efficient and accurate when A is the next template base. In contrast, extension occurs less efficiently and accurately when T is the target template base. A striking exception occurs during extension of a G:T mispair, where the enzyme switches specificity, "preferring" to make a correct A:T base pair immediately downstream from an originally favored G:T mispair. Polymerase iota  generates a variety of single and tandem mispairs with high frequency, implying that it may act as a strong mutator when copying undamaged DNA templates in vivo. Even so, its limited ability to catalyze extension from a relatively stable primer/template containing a "buried" mismatch suggests that polymerase iota -catalyzed errors are confined to short template regions.

* This work was supported by the National Institutes of Health Intramural research program (A. V., A. T., E. G. F., and R. W.) and by National Institutes of Health Grants GM21422 and GM42554 (to M. F. G.).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.

§ Present address: UPR 9003, CNRS, Cancérogenèse et Mutagenèse Moléculaire et Structurale, ESBS, Blvd. S. Brant, 67400 Strasbourg, France.

|| To whom correspondence should be addressed: Section on DNA Replication Repair and Mutagenesis, Bldg. 6, Rm. 1A13, National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-2725. Tel.: 301-496-6175; Fax: 301-594-1135; E-mail: woodgate@helix.nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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