Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replicationin Vivo
Open accessAbstract
Friedreich ataxia (FRDA) is associated with the expansion of a GAA. TTC triplet repeat in the first intron of the frataxin gene, resulting in reduced levels of frataxin mRNA and protein. To investigate the mechanisms by which the intronic expansion produces its effect, GAA.TTC repeats of various lengths (9 to 270 triplets) were cloned in both orientations in the intron of a reporter gene. Plasmids containing these repeats were transiently transfected into COS-7 cells. A length- and orientation-dependent inhibition of reporter gene expression was observed. RNase protection and Northern blot analyses showed very low levels of mature mRNA when longer GAA repeats were transcribed, with no accumulation of primary transcript. Replication of plasmids carrying long GAA.TTC tracts (approximately 250 triplets) was greatly inhibited in COS-7 cells compared with plasmids carrying (GAA.TTC)9 and (GAA.TTC)90. Replication inhibition was five times greater for the plasmid whose transcript contains (GAA)230 than for the plasmid whose transcript contains (UUC)270. Our in vivo investigation revealed that expanded GAA.TTC repeats from intron I of the FRDA gene inhibit transcription rather than post-transcriptional RNA processing and also interfere with replication. The molecular basis for these effects may be the formation of non-B DNA structures.
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Cites
Molecular Cloning: A Laboratory Manual
Sambrook, J., Fritsch, E., & Maniatis, T. (1989) · UCLA - Biblioteca de Ciencias de la Salud · Cited by 133,589 · see citing works
Molecular cloning: A laboratory manual
Deininger, P. L. (1990) · Analytical Biochemistry · doi:10.1016/0003-2697(90)90595-z · Cited by 84,684 · see citing works
Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion
Campuzano, V., Montermini, L., Moltò, M. D., Pianese, L., Cossée, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., et al. (1996) · Science · doi:10.1126/science.271.5254.1423 · Cited by 2,786 · see citing works
Self-citationClinical and Genetic Abnormalities in Patients with Friedreich's Ataxia
Dürr, A., Cossee, M., Agid, Y., Campuzano, V., Mignard, C., Penet, C., Mandel, J.-L., Brice, A., & Koenig, M. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610173351601 · Cited by 1,071 · see citing works
Frataxin is Reduced in Friedreich Ataxia Patients and is Associated with Mitochondrial Membranes
Campuzano, V., Montermini, L., Lutz, Y., Cova, L., Hindelang, C., Jiralerspong, S., Trottier, Y., Kish, S. J., Faucheux, B. A., Trouillas, P., et al. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.11.1771 · Cited by 739 · see citing works
Self-citationSCA1 transgenic mice: A model for neurodegeneration caused by an expanded CAG trinucleotide repeat
Burright, E. N., Clark, H. B., Servadio, A., Matilla‐Dueñas, A., Feddersen, R. M., Yunis, W. S., Duvick, L. A., Zoghbi, H. Y., & Orr, H. T. (1995) · Cell · doi:10.1016/0092-8674(95)90273-2 · Cited by 596 · see citing works
Trinucleotide repeats that expand in human disease form hairpin structures in vitro
Gacy, A. M., Goellner, G. M., Juranić, N., Macura, S. I., & McMurray, C. T. (1995) · Cell · doi:10.1016/0092-8674(95)90074-8 · Cited by 569 · see citing works
Exon amplification: a strategy to isolate mammalian genes based on RNA splicing.
Buckler, A., Chang, D. D., Graw, S. L., Brook, J. D., Haber, D. A., Sharp, P. A., & Housman, D. E. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.9.4005 · Cited by 419 · see citing works
Kang, S., Jaworski, A., Ohshima, K., & Wells, R. D. (1995) · Nature Genetics · doi:10.1038/ng0695-213 · Cited by 355 · see citing works
Self-citationTrinucleotide repeats affect DNA replication in vivo
Samadashwily, G., Raca, G., & Mirkin, S. (1997) · Nature Genetics · doi:10.1038/ng1197-298 · Cited by 343 · see citing works
Trinucleotide repeats in neurogenetic disorders.
Paulson, H., & Fischbeck, K. (1996) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.19.030196.000455 · Cited by 323 · see citing works
Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation
Mangiarini, L., Sathasivam, K., Mahal, A., Mott, R., Seller, M. J., & Bates, G. P. (1997) · Nature Genetics · doi:10.1038/ng0297-197 · Cited by 318 · see citing works
Molecular Basis of Genetic Instability of Triplet Repeats
Wells, R. D. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.6.2875 · Cited by 303 · see citing works
Self-citationTrinucleotide repeats associated with human disease
Mitas, M. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.12.2245 · Cited by 294 · see citing works
Genetic instabilities and hereditary neurological diseases
Wells, R. D., Warren, S. T., & Sarmiento, M. (1998) · Cited by 270 · see citing works
Self-citationMirkin, S. M., & Frank-Kamenet︠s︡kiĭ, M. D. (1994) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.bb.23.060194.002545 · Cited by 258 · see citing works
Genetic Instabilities and Hereditary Neurological Diseases
Opal, P., & Paulson, H. L. (1998) · The American Journal of Human Genetics · doi:10.1086/302134 · Cited by 250 · see citing works
Induction of RNA-stabilized DMA conformers by transcription of an immunoglobulin switch region
Reaban, M. E., & Griffin, J. A. (1990) · Nature · doi:10.1038/348342a0 · Cited by 246 · see citing works
Usdin, K., & Woodford, K. J. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.20.4202 · Cited by 241 · see citing works
Stavnezer, J. (1991) · Nature · doi:10.1038/351447b0 · Cited by 235 · see citing works
Association of fragile X syndrome with delayed replication of the FMR1 gene
Hansen, R. S., Canfield, T. K., Lamb, M. M., Gartler, S. M., & Laird, C. D. (1993) · Cell · doi:10.1016/0092-8674(93)90365-w · Cited by 234 · see citing works
Stability of a CTG/CAG Trinucleotide Repeat in Yeast Is Dependent on Its Orientation in the Genome
Freudenreich, C. H., Stavenhagen, J. B., & Zakian, V. A. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.4.2090 · Cited by 219 · see citing works
The Friedreich ataxia GAA triplet repeat: premutation and normal alleles
Montermini, L. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.8.1261 · Cited by 208 · see citing works
Self-citationKang, S., Ohshima, K., Shimizu, M., Amirhaeri, S., & Wells, R. D. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.45.27014 · Cited by 184 · see citing works
Self-citationJaworski, A., Rosche, W. A., Gellibolian, R., Kang, S.-J., Shimizu, M., Bowater, R. P., Sinden, R. R., & Wells, R. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.24.11019 · Cited by 156 · see citing works
Self-citationHuman Tumor Necrosis Factor Receptor p75/80 (CD120b) Gene Structure and Promoter Characterization
Santee, S. M., & Owen‐Schaub, L. B. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.35.21151 · Cited by 144 · see citing works
Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice
Bingham, P., Scott, M., Wang, S.-P., Mcphaul, M., Wilson, E., Garbern, J., Merry, D., & Fischbeck, K. (1995) · Nature Genetics · doi:10.1038/ng0295-191 · Cited by 144 · see citing works
Hypermutable myotonic dystrophy CTG repeats in transgenic mice
Monckton, D., Coolbaugh, M. I., Ashizawa, K. T., Siciliano, M., & Caskey, C. (1997) · Nature Genetics · doi:10.1038/ng0297-193 · Cited by 142 · see citing works
Bidichandani, S. I., Ashizawa, T., & Patel, P. I. (1997) · Europe PMC (PubMed Central) · Cited by 141 · see citing works
Reaban, M. E., Lebowitz, J., & Griffin, J. A. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31881-1 · Cited by 136 · see citing works
Moderate intergenerational and somatic instability of a 55-CTG repeat in transgenic mice
Gourdon, G., Radvanyi, F., Lia, A., Duros, C., Blanche, M., Abitbol, M. M., Junien, C., & Hofmann-Radvanyi, H. (1997) · Nature Genetics · doi:10.1038/ng0297-190 · Cited by 128 · see citing works
Orientation dependence of trinucleotide CAG repeat instability in Saccharomyces cerevisiae
Maurer, D. J., O'Callaghan, B. L., & Livingston, D. M. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.12.6617 · Cited by 123 · see citing works
Minisatellite mutation rate variation associated with a flanking DNA sequence polymorphism
Monckton, D. G., Neumann, R., Guram, T., Fretwell, N., Tamaki, K., MacLeod, A., & Jeffreys, A. J. (1994) · Nature Genetics · doi:10.1038/ng1094-162 · Cited by 118 · see citing works
Increased trinucleotide repeat instability with advanced maternal age.
Kaytor, M., Burright, E., Duvick, L., Zoghbi, H., & Orr, H. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.12.2135 · Cited by 106 · see citing works
Altered gene expression correlates with DNA structure.Preprint
Kohwi, Y., & Kohwi-shigematsu, T. (1991) · Genes & Development · doi:10.1101/gad.5.12b.2547 · Cited by 101 · see citing works
Cloning, Characterization, and Properties of Seven Triplet Repeat DNA Sequences
Ohshima, K., Kang, S., Larson, J. E., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.28.16773 · Cited by 99 · see citing works
Self-citationOhshima, K., & Wells, R. D. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.27.16798 · Cited by 95 · see citing works
Self-citationBowater, R. P. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.14.2861 · Cited by 92 · see citing works
Instability of CAG and CTG Trinucleotide Repeats in Saccharomyces cerevisiae
Miret, J. J., Pessoa-Brandão, L., & Lahue, R. S. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.6.3382 · Cited by 87 · see citing works
Shimizu, M., Gellibolian, R., Oostra, B. A., & Wells, R. D. (1996) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0273 · Cited by 78 · see citing works
Self-citationA Long Purine-Pyrimidine Homopolymer Acts as a Transcriptional Diode
Grabczyk, E., & Fishman, M. C. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.4.1791 · Cited by 76 · see citing works
Relationship Between Growth and Deletions of CTG·CAG Triplet Repeats in Plasmids
Bowater, R. P., Rosche, W. A., Jaworski, A., et al. (1996) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0625 · Cited by 67 · see citing works
Cossée, M., Campuzano, V., Koutníková, H., Fischbeck, K., Mandel, J., Koenig, M., Bidichandani, S. I., Patel, P. I., Moltè, M. D., Cañizares, J., et al. (1997) · Nature Genetics · doi:10.1038/ng0497-337 · Cited by 61 · see citing works
Self-citationMandel, J. (1997) · Nature · doi:10.1038/386767a0 · Cited by 57 · see citing works
Collier, D. A., & Wells, R. D. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)86996-4 · Cited by 56 · see citing works
Self-citationIntramolecular triplex potential sequence within a gene down regulates its expressionin vivo
Sarkar, P. S., & Brahmachari, S. K. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.21.5713 · Cited by 49 · see citing works
Ohshima, K., Kang, S., & Wells, R. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.4.1853 · Cited by 47 · see citing works
Self-citationDNA triplet repeats and neurologic disease.
Rosenberg, R. N. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610173351609 · Cited by 46 · see citing works
Rosche, W. A., Jaworski, A., Kang, S.-J., Kramer, S. F., Larson, J. E., Geidroc, D. P., Wells, R. D., & Sinden, R. R. (1996) · Journal of Bacteriology · doi:10.1128/jb.178.16.5042-5044.1996 · Cited by 44 · see citing works
Self-citationLavedan, C. N., Garrett, L. J., & Nussbaum, R. L. (1997) · Human Genetics · doi:10.1007/s004390050525 · Cited by 39 · see citing works
Aoki, T., Koch, K. S., & Leffert, H. L. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.0890 · Cited by 29 · see citing works
Beard, C., Amand, J. S., & Astell, C. R. (1989) · Virology · doi:10.1016/0042-6822(89)90211-0 · Cited by 28 · see citing works
Andreassen, R., Egeland, T., & Olaisen, B. (1996) · PubMed · Cited by 19 · see citing works
Amirhaeri, S., Wohlrab, F., & Wells, R. D. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.7.3313 · Cited by 8 · see citing works
Self-citationA trinucleotide repeat combination polymorphism in the cardiac alpha myosin heavy chain (MYH6) gene
van den Berg, M. H., Meijer, H., & Geraedts, J. P. M. (1995) · Human Genetics · doi:10.1007/bf00209499 · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Buckler, A. L., Chang, D. D., Graw, S. L., Brook, J. D., Haber, D. A., Sharp, P. A., and Housman, D. E. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 4005-4009
- Jaworski, A., Rosche, W. A., Gellibolian, R., Kang, S., Shimizu, M., Bowater, R. P., Sinden, R. R., and Wells, R. D. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 11019 -11023
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Mirkin, E. V., & Mirkin, S. M. (2007) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00030-06 · Cited by 482 · see citing works
Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia
Herman, D., Jenssen, K., Burnett, R., Soragni, E., Perlman, S. L., & Gottesfeld, J. M. (2006) · Nature Chemical Biology · doi:10.1038/nchembio815 · Cited by 442 · see citing works
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Sakamoto, N., Chastain, P. D., Parniewski, P., Ohshima, K., Pandolfo, M., Griffith, J. D., & Wells, R. D. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80474-8 · Cited by 313 · see citing works
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Miranda, C. J., Santos, M. M., Ohshima, K., Smith, J., Li, L., Bunting, M., Cossée, M., Koenig, M., Sequeiros, J., Kaplan, J., et al. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02251-2 · Cited by 172 · see citing works
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Sommers, J. A., Rawtani, N., Gupta, R., Bugreev, D. V., Mazin, A. V., Cantor, S. B., & Brosh, R. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809019200 · Cited by 112 · see citing works
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Self-citation
- Authors
- Ohshima, K., Montermini, L., Wells, R. D., & Pandolfo, M.
- Affiliations
- Hôpital Notre-Dame (CA)
- Texas Medical Center (US)
- Corresponding author
- Pandolfo, Massimo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-06
- Volume
- 273
- Issue
- 23
- Pages
- 14588-14595
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2137770909
- Cited by
- 302
- References
- 55
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 8 · 2021: 3 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 12 · 2015: 12 · 2014: 11 · 2013: 12 · 2012: 6
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Welch Foundation
- Muscular Dystrophy Association
- Medical Research Council Canada
- National Institutes of Health (7r01ns034192-06)
- Medical Research Council
- National Institute of Neurological Disorders and Stroke (NS34192)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- Friedreich's ataxia, frataxin gene, transcription inhibition, DNA replication inhibition, non-B DNA structures, RNA processing, reporter gene expression
- MeSH terms
- Frataxin, Animals, Cloning, Molecular, DNA Replication, Friedreich Ataxia, Gene Expression Regulation, Humans, Nucleic Acid Conformation, Plasmids, RNA, Messenger, Transcription, Genetic, Transfection, Phosphotransferases (Alcohol Group Acceptor), Genes, Reporter, Trinucleotide Repeats, COS Cells, Iron-Binding Proteins
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