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Mol. Cell. Biol., Apr 1997, 2090-2098, Vol 17, No. 4
Copyright © 1997, American Society for Microbiology

Stability of a CTG/CAG trinucleotide repeat in yeast is dependent on its orientation in the genome

CH Freudenreich, JB Stavenhagen and VA Zakian
Department of Molecular Biology, Princeton University, New Jersey 08544, USA.

Trinucleotide repeat expansion is the causative mutation for a growing number of diseases including myotonic dystrophy, Huntington's disease, and fragile X syndrome. A (CTG/CAG)130 tract cloned from a myotonic dystrophy patient was inserted in both orientations into the genome of Saccharomyces cerevisiae. This insertion was made either very close to the 5' end or very close to the 3' end of a URA3 transcription unit. Regardless of its orientation, no evidence was found for triplet- mediated transcriptional repression of the nearby gene. However, the stability of the tract correlated with its orientation on the chromosome. In one orientation, the (CTG/CAG)130 tract was very unstable and prone to deletions. In the other orientation, the tract was stable, with fewer deletions and two possible cases of expansion detected. Analysis of the direction of replication through the region showed that in the unstable orientation the CTG tract was on the lagging-strand template and that in the stable orientation the CAG tract was on the lagging-strand template. The orientation dependence of CTG/CAG tract instability seen in this yeast system supports models involving hairpin-mediated polymerase slippage previously proposed for trinucleotide repeat expansion.

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• Wojciechowska, M., Bacolla, A., Larson, J. E., Wells, R. D. (2005). The Myotonic Dystrophy Type 1 Triplet Repeat Sequence Induces Gross Deletions and Inversions. J. Biol. Chem. 280: 941-952 [Abstract] [Full Text]  
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• Nag, D. K., Suri, M., Stenson, E. K. (2004). Both CAG repeats and inverted DNA repeats stimulate spontaneous unequal sister-chromatid exchange in Saccharomyces cerevisiae. Nucleic Acids Res 32: 5677-5684 [Abstract] [Full Text]  
• Dere, R., Napierala, M., Ranum, L. P. W., Wells, R. D. (2004). Hairpin Structure-forming Propensity of the (CCTG{middle dot}CAGG) Tetranucleotide Repeats Contributes to the Genetic Instability Associated with Myotonic Dystrophy Type 2. J. Biol. Chem. 279: 41715-41726 [Abstract] [Full Text]  
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• Napierala, M., Parniewski, P., Pluciennik, A., Wells, R. D. (2002). Long CTG{middle dot}CAG Repeat Sequences Markedly Stimulate Intramolecular Recombination. J. Biol. Chem. 277: 34087-34100 [Abstract] [Full Text]  
• Henricksen, L. A., Veeraraghavan, J., Chafin, D. R., Bambara, R. A. (2002). DNA Ligase I Competes with FEN1 to Expand Repetitive DNA Sequences in Vitro. J. Biol. Chem. 277: 22361-22369 [Abstract] [Full Text]  
• Panigrahi, G. B., Cleary, J. D., Pearson, C. E. (2002). In Vitro (CTG){middle dot}(CAG) Expansions and Deletions by Human Cell Extracts. J. Biol. Chem. 277: 13926-13934 [Abstract] [Full Text]  
• Schweitzer, J. K., Reinke, S. S., Livingston, D. M. (2001). Meiotic Alterations in CAG Repeat Tracts. Genetics 159: 1861-1865 [Abstract] [Full Text]  
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• Rolfsmeier, M. L., Dixon, M. J., Pessoa-Brandão, L., Pelletier, R., Miret, J. J., Lahue, R. S. (2001). Cis-Elements Governing Trinucleotide Repeat Instability in Saccharomyces cerevisiae. Genetics 157: 1569-1579 [Abstract] [Full Text]  
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• Nozawa, K., Suzuki, M., Takemura, M., Yoshida, S. (2000). In vitro expansion of mammalian telomere repeats by DNA polymerase {alpha}-primase. Nucleic Acids Res 28: 3117-3124 [Abstract] [Full Text]  
• Ireland, M. J., Reinke, S. S., Livingston, D. M. (2000). The Impact of Lagging Strand Replication Mutations on the Stability of CAG Repeat Tracts in Yeast. Genetics 155: 1657-1665 [Abstract] [Full Text]  
• Seznec, H., Lia-Baldini, A.-S., Duros, C., Fouquet, C., Lacroix, C., Hofmann-Radvanyi, H., Junien, C., Gourdon, G. (2000). Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability. Hum Mol Genet 9: 1185-1194 [Abstract] [Full Text]  
• Jin, P., Warren, S. T. (2000). Understanding the molecular basis of fragile X syndrome. Hum Mol Genet 9: 901-908 [Abstract] [Full Text]  
• Young, E. T., Sloan, J. S., Van Riper, K. (2000). Trinucleotide Repeats Are Clustered in Regulatory Genes in Saccharomyces cerevisiae. Genetics 154: 1053-1068 [Abstract] [Full Text]  
• Iyer, R. R., Pluciennik, A., Rosche, W. A., Sinden, R. R., Wells, R. D. (2000). DNA Polymerase III Proofreading Mutants Enhance the Expansion and Deletion of Triplet Repeat Sequences in Escherichia coli. J. Biol. Chem. 275: 2174-2184 [Abstract] [Full Text]  
• Balakumaran, B. S., Freudenreich, C. H., Zakian, V. A. (2000). CGG/CCG repeats exhibit orientation-dependent instability and orientation-independent fragility in Saccharomyces cerevisiae. Hum Mol Genet 9: 93-100 [Abstract] [Full Text]  
• Rolfsmeier, M. L., Lahue, R. S. (2000). Stabilizing Effects of Interruptions on Trinucleotide Repeat Expansions in Saccharomyces cerevisiae. Mol. Cell. Biol. 20: 173-180 [Abstract] [Full Text]  
• Karthikeyan, G., Chary, K. V., Rao, B. J. (1999). Fold-back structures at the distal end influence DNA slippage at the proximal end during mononucleotide repeat expansions. Nucleic Acids Res 27: 3851-3858 [Abstract] [Full Text]  
• Jakupciak, J. P., Wells, R. D. (1999). Genetic Instabilities in (CTG{middle dot}CAG) Repeats Occur by Recombination. J. Biol. Chem. 274: 23468-23479 [Abstract] [Full Text]  
• Schweitzer, J. K., Livingston, D. M. (1999). The Effect of DNA Replication Mutations on CAG Tract Stability in Yeast. Genetics 152: 953-963 [Abstract] [Full Text]  
• Cohen, H., Sears, D. D., Zenvirth, D., Hieter, P., Simchen, G. (1999). Increased Instability of Human CTG Repeat Tracts on Yeast Artificial Chromosomes during Gametogenesis. Mol. Cell. Biol. 19: 4153-4158 [Abstract] [Full Text]  
• Paques, F., Haber, J. E. (1999). Multiple Pathways of Recombination Induced by Double-Strand Breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 63: 349-404 [Abstract] [Full Text]  
• McMurray, C. T. (1999). DNA secondary structure: A common and causative factor for expansion in human disease. Proc. Natl. Acad. Sci. USA 96: 1823-1825 [Full Text]  
• Moore, H., Greenwell, P. W., Liu, C.-P., Arnheim, N., Petes, T. D. (1999). Triplet repeats form secondary structures that escape DNA repair in yeast. Proc. Natl. Acad. Sci. USA 96: 1504-1509 [Abstract] [Full Text]  
• Iyer, R. R., Wells, R. D. (1999). Expansion and Deletion of Triplet Repeat Sequences in Escherichia coli Occur on the Leading Strand of DNA Replication. J. Biol. Chem. 274: 3865-3877 [Abstract] [Full Text]  
• Suo, Z., Johnson, K. A. (1998). DNA Secondary Structure Effects on DNA Synthesis Catalyzed by HIV-1 Reverse Transcriptase. J. Biol. Chem. 273: 27259-27267 [Abstract] [Full Text]  
• Miret, J. J., Pessoa-Brandao, L., Lahue, R. S. (1998). Orientation-dependent and sequence-specific expansions of CTG/CAG trinucleotide repeats in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 95: 12438-12443 [Abstract] [Full Text]  
• Maurer, D. J., O'Callaghan, B. L., Livingston, D. M. (1998). Mapping the Polarity of Changes That Occur in Interrupted CAG Repeat Tracts in Yeast. Mol. Cell. Biol. 18: 4597-4604 [Abstract] [Full Text]  
• Wells, R. D., Parniewski, P., Pluciennik, A., Bacolla, A., Gellibolian, R., Jaworski, A. (1998). Small Slipped Register Genetic Instabilities in Escherichia coli in Triplet Repeat Sequences Associated with Hereditary Neurological Diseases. J. Biol. Chem. 273: 19532-19541 [Abstract] [Full Text]  
• Ohshima, K., Montermini, L., Wells, R. D., Pandolfo, M. (1998). Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replication in Vivo. J. Biol. Chem. 273: 14588-14595 [Abstract] [Full Text]  
• Lobachev, K. S., Shor, B. M., Tran, H. T., Taylor, W., Keen, J. D., Resnick, M. A., Gordenin, D. A. (1998). Factors Affecting Inverted Repeat Stimulation of Recombination and Deletion in Saccharomyces cerevisiae. Genetics 148: 1507-1524 [Abstract] [Full Text]  
• Freudenreich, C. H., Kantrow, S. M., Zakian, V. A. (1998). Expansion and Length-Dependent Fragility of CTG Repeats in Yeast. Science 279: 853-856 [Abstract] [Full Text]  
• Ohshima, K., Wells, R. D. (1997). Hairpin Formation during DNA Synthesis Primer Realignment in Vitro in Triplet Repeat Sequences from Human Hereditary Disease Genes. J. Biol. Chem. 272: 16798-16806 [Abstract] [Full Text]  
• Pluciennik, A., Iyer, R. R., Parniewski, P., Wells, R. D. (2000). Tandem Duplication. A NOVEL TYPE OF TRIPLET REPEAT INSTABILITY. J. Biol. Chem. 275: 28386-28397 [Abstract] [Full Text]  
• Bacolla, A., Jaworski, A., Connors, T. D., Wells, R. D. (2001). PKD1 Unusual DNA Conformations Are Recognized by Nucleotide Excision Repair. J. Biol. Chem. 276: 18597-18604 [Abstract] [Full Text]  
• Henricksen, L. A., Tom, S., Liu, Y., Bambara, R. A. (2000). Inhibition of Flap Endonuclease 1 by Flap Secondary Structure and Relevance to Repeat Sequence Expansion. J. Biol. Chem. 275: 16420-16427 [Abstract] [Full Text]  
• Jankowski, C., Nasar, F., Nag, D. K. (2000). Meiotic instability of CAG repeat tracts occurs by double-strand break repair in yeast. Proc. Natl. Acad. Sci. USA 97: 2134-2139 [Abstract] [Full Text]