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Originally published In Press as doi:10.1074/jbc.M910272199 on April 3, 2000

J. Biol. Chem., Vol. 275, Issue 24, 18382-18390, June 16, 2000
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Base Stacking and Even/Odd Behavior of Hairpin Loops in DNA Triplet Repeat Slippage and Expansion with DNA Polymerase*

Michael J. Hartenstine, Myron F. GoodmanDagger , and John Petruska

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

Repetitions of CAG or CTG triplets in DNA can form intrastrand hairpin loops with combinations of normal and mismatched base pairs that easily rearrange. Such loops may promote primer-template slippage in DNA replication or repair to give triplet-repeat expansions like those associated with neurodegenerative diseases. Using self-priming sequences (e.g. (CAG)16(CTG)4), we resolve all hairpin loops formed and measure their slippage and expansion rates with DNA polymerase at 37 °C. Comparing CAG/CTG loop structures with GAC/GTC structures, having similar hydrogen bonding but different base stacking, we find that CAG, CTG, and GTC triplets predominantly form even-membered loops that slip in steps of two triplets, whereas GAC triplets favor odd-numbered loops. Slippage rates decline as hairpin stability increases, supporting the idea that slippage initiates more easily in less stable regions. Loop stabilities (in low salt) increase in the order GTC < CAG < GAC < CTG, while slippage rates decrease in the order GTC > CAG approx  GAC > CTG. Loops of GTC compared with CTG melt 9 °C lower and slip 6-fold faster. We interpret results in terms of base stacking, by relating melting temperature to standard enthalpy changes for doublets of base pairs and mispairs, considering enthalpy-entropy compensation.

* This work was supported by National Institutes of Health (NIH) Grants AG 11398 and GM 21422 and National Institute on Aging, NIH, Program Project Grant AG17179.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.

Dagger To whom correspondence should be addressed: Dept. of Biological Sciences, University of Southern California, SHS Rm. 172, University Park, Los Angeles, CA 90089-1340. Tel.: 213-740-5190; Fax: 213-740-8631; E-mail: mgoodman@mizar.usc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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