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J. Biol. Chem., Vol. 280, Issue 45, 37366-37376, November 11, 2005

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Increased Negative Superhelical Density in Vivo Enhances the Genetic Instability of Triplet Repeat Sequences^*

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

The influence of negative superhelical density on the genetic instabilities of long GAA·TTC, CGG·CCG, and CTG·CAG repeat sequences was studied in vivo in topologically constrained plasmids in Escherichia coli. These repeat tracts are involved in the etiologies of Friedreich ataxia, fragile X syndrome, and myotonic dystrophy type 1, respectively. The capacity of these DNA tracts to undergo deletions-expansions was explored with three genetic-biochemical approaches including first, the utilization of topoisomerase I and/or DNA gyrase mutants, second, the specific inhibition of DNA gyrase by novobiocin, and third, the genetic removal of the HU protein, thus lowering the negative supercoil density (–). All three strategies revealed that higher – in vivo enhanced the formation of deleted repeat sequences. The effects were most pronounced for the Friedreich ataxia and the fragile X triplet repeat sequences. Higher levels of – stabilize non-B DNA conformations (i.e. triplexes, sticky DNA, flexible and writhed DNA, slipped structures) at appropriate repeat tracts; also, numerous prior genetic instability investigations invoke a role for these structures in promoting the slippage of the DNA complementary strands. Thus, we propose that the in vivo modulation of the DNA structure, localized to the repeat tracts, is responsible for these behaviors. Presuming that these interrelationships are also found in humans, dynamic alterations in the chromosomal nuclear matrix may modulate the – of certain DNA regions and, thus, stabilize/destabilize certain non-B conformations which regulate the genetic expansions-deletions responsible for the diseases.

Received for publication, July 22, 2005 , and in revised form, September 13, 2005.

^* This research was supported by National Institutes of Health Grant ES11347 and grants from the Robert A. Welch Foundation and the Friedreich Ataxia Research Alliance–Seek a Miracle (Muscular Dystrophy Association). 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.

¹ 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.tamhsc.edu.

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