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J. Biol. Chem., Vol. 279, Issue 44, 45360-45368, October 29, 2004

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To Slip or Skip, Visualizing Frameshift Mutation Dynamics for Error-prone DNA Polymerases^*

Brigette Tippin, Sawami Kobayashi, Jeffrey G. Bertram, and Myron F. Goodman

From the Departments of Biological Sciences and Chemistry, Hedco Molecular Biology Laboratories, University of Southern California, Los Angeles, California 90089-1340

Three models describing frameshift mutations are "classical" Streisinger slippage, proposed for repetitive DNA, and "misincorporatation misalignment" and "dNTP-stabilized misalignment," proposed for non-repetitive DNA. We distinguish between models using pre-steady state fluorescence kinetics to visualize transiently misaligned DNA intermediates and nucleotide incorporation products formed by DNA polymerases adept at making small frameshift mutations in vivo. Human polymerase (pol) µ catalyzes Streisinger slippage exclusively in repetitive DNA, requiring as little as a dinucleotide repeat. Escherichia coli pol IV uses dNTP-stabilized misalignment in identical repetitive DNA sequences, revealing that pol µ and pol IV use different mechanisms in repetitive DNA to achieve the same mutational end point. In non-repeat sequences, pol µ switches to dNTP-stabilized misalignment. pol generates –1 frameshifts in "long" repeats and base substitutions in "short" repeats. Thus, two polymerases can use two different frameshift mechanisms on identical sequences, whereas one polymerase can alternate between frameshift mechanisms to process different sequences.

Received for publication, July 29, 2004 , and in revised form, August 30, 2004.

^* This work was supported by National Institutes of Health Grants GM21422 and ES012259. The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Dept. of Biological Sciences, SHS172, University Park, University of Southern California, Los Angeles, CA 90089-1340. Tel.: 213-740-5190; Fax: 213-740-8631; E-mail: mgoodman{at}usc.edu.

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