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J. Biol. Chem., Vol. 281, Issue 38, 27950-27955, September 22, 2006

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(CAG)·(CTG) Repeats Associated with Neurodegenerative Diseases Are Stable in the Escherichia coli Chromosome^*

Seung-Hwan Kim, Magorzata J. Pytlos, William A. Rosche, and Richard R. Sinden¹

From the Laboratory of DNA Structure and Mutagenesis, Center for Genome Research, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas, 77030-3303 and the Department of Biological Science, University of Tulsa, Tulsa, Oklahoma 74104-3126

(CAG)_n·(CTG)_n expansion is associated with many neurodegenerative diseases. Repeat instability has been extensively studied in bacterial plasmids, where repeats undergo deletion at high rates. We report an assay for (CAG)_n·(CTG)_n deletion from the chloramphenicol acetyltransferase gene integrated into the Escherichia coli chromosome. In strain AB1157, deletion rates for 25–60 (CAG)·(CTG) repeats integrated in the chromosome ranged from 6.88 x 10^–9 to 1.33 x 10^–10, or 6,300 to 660,000-fold lower than in plasmid pBR325. In contrast to the situation in plasmids, deletions occur at a higher rate when (CTG)₄₃, rather than (CAG)₄₃, comprised the leading template strand, and complete rather than partial deletions were the predominant mutation observed. Repeats were also stable on long term growth following multiple passages through exponential and stationary phase. Mutations in priA and recG increased or decreased deletion rates, but repeats were still greatly stabilized in the chromosome. The remarkable stability of (CAG)_n·(CTG)_n repeats in the E. coli chromosome may result from the differences in the mechanisms for replication or the probability for recombination afforded by a high plasmid copy number. The integration of (CAG)_n·(CTG)_n repeats into the chromosome provides a model system in which the inherent stability of these repeats reflects that in the human genome more closely.

Received for publication, February 6, 2006 , and in revised form, June 22, 2006.

^* This work was supported by National Institutes of Environmental Health Sciences Grant ES05508 (to R. R. S.). 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: Laboratory of DNA Structure and Mutagenesis, Dept. of Biological Sciences, Florida Institute of Technology, 150 W. University Blvd., Melbourne, FL 32901-6975. Tel.: 321-674-8576; Fax: 321-674-7238; E-mail: Rsinden{at}fit.edu.

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