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J. Biol. Chem., Vol. 279, Issue 8, 6444-6454, February 20, 2004

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Structure-dependent Recombination Hot Spot Activity of GAA·TTC Sequences from Intron 1 of the Friedreich's Ataxia Gene^*

Marek Napierala, Ruhee Dere, Alexandre Vetcher, and Robert D. Wells

From the Institute of Biosciences and Technology, Center for Genome Research, Texas A&M University System Health Science Center, Texas Medical Center, Houston, Texas 77030-3303

The recombinational properties of long GAA·TTC repeating sequences were analyzed in Escherichia coli to gain further insights into the molecular mechanisms of the genetic instability of this tract as possibly related to the etiology of Friedreich's ataxia. Intramolecular and intermolecular recombination studies showed that the frequency of recombination between the GAA·TTC tracts was as much as 15 times higher than the non-repeating control sequences. Homologous, intramolecular recombination between GAA·TTC tracts and GAAGGA·TCCTTC repeats also occurred with a very high frequency (0.8%). Biochemical analyses of the recombination products demonstrated the expansions and deletions of the GAA·TTC repeats. These results, together with our previous studies on the CTG·CAG sequences, suggest that the recombinational hot spot characteristics may be a common feature of all triplet repeat sequences. Unexpectedly, we found that the recombination properties of the GAA·TTC tracts were unique, compared with CTG·CAG repeats, because they depended on the DNA secondary structure polymorphism. Increasing the length of the GAA·TTC repeats decreased the intramolecular recombination frequency between these tracts. Also, a correlation was found between the propensity of the GAA·TTC tracts to adopt the sticky DNA conformation and the inhibition of intramolecular recombination. The use of novobiocin to modulate the intracellular DNA topology, i.e. the lowering of the negative superhelical density, repressed the formation of the sticky DNA structure, thereby restoring the expected positive correlation between the length of the GAA·TTC tracts and the frequency of intramolecular recombination. Hence, our results demonstrate that sticky DNA exists and functions in E. coli.

Received for publication, August 28, 2003 , and in revised form, November 17, 2003.

^* This work was supported by National Institutes of Health Grants NS37554 and ES11347, the Robert A. Welch Foundation, and the Friedreich's Ataxia Research Alliance. 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.

Present address: Dept. of Molecular and Cell Biology, the University of Texas at Dallas, Mail Station F03.1, Richardson, TX 75083.

To whom correspondence should be addressed: Center for Genome Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, 2121 W. Holcombe Blvd. Houston, TX 77030-3303. Tel.: 713-677-7651; Fax: 713-677-7689; E-mail: rwells{at}ibt.tamu.edu.

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