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J. Biol. Chem., Vol. 279, Issue 40, 41715-41726, October 1, 2004

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Hairpin Structure-forming Propensity of the (CCTG·CAGG) Tetranucleotide Repeats Contributes to the Genetic Instability Associated with Myotonic Dystrophy Type 2^*

Ruhee Dere, Marek Napierala, Laura P. W. Ranum, 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 and the Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455

The genetic instabilities of (CCTG·CAGG)_n tetranucleotide repeats were investigated to evaluate the molecular mechanisms responsible for the massive expansions found in myotonic dystrophy type 2 (DM2) patients. DM2 is caused by an expansion of the repeat from the normal allele of 26 to as many as 11,000 repeats. Genetic expansions and deletions were monitored in an African green monkey kidney cell culture system (COS-7 cells) as a function of the length (30, 114, or 200 repeats), orientation, or proximity of the repeat tracts to the origin (SV40) of replication. As found for CTG·CAG repeats related to DM1, the instabilities were greater for the longer tetranucleotide repeat tracts. Also, the expansions and deletions predominated when cloned in orientation II (CAGG on the leading strand template) rather than I and when cloned proximal rather than distal to the replication origin. Biochemical studies on synthetic d(CAGG)₂₆ and d(CCTG)₂₆ as models of unpaired regions of the replication fork revealed that d(CAGG)₂₆ has a marked propensity to adopt a defined base paired hairpin structure, whereas the complementary d(CCTG)₂₆ lacks this capacity. The effect of orientation described above differs from all previous results with three triplet repeat sequences (including CTG·CAG), which are also involved in the etiologies of other hereditary neurological diseases. However, similar to the triplet repeat sequences, the ability of one of the two strands to form a more stable folded structure, in our case the CAGG strand, explains this unorthodox "reversed" behavior.

Received for publication, June 9, 2004 , and in revised form, July 21, 2004.

^* This work was supported by National Institutes of Health Grants NS37554 and ES11347, the Robert A. Welch Foundation, and the Muscular Dystrophy (Seek a Miracle) Association (to R. D. W.) and National Institutes of Health Grant NS35870 and a grant from the Muscular Dystrophy Association (to L. P. W. R.). 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: 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.tamushsc.edu.

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