Repeat instability as the basis for human diseases and as a potential target for therapy
Abstract
Expansions of repetitive DNA sequences cause numerous human neurological and neuromuscular diseases. Ongoing repeat expansions in patients can exacerbate disease progression and severity. As pathogenesis is connected to repeat length, a potential therapeutic avenue is to modulate disease by manipulating repeat expansion size--targeting DNA, the root-cause of symptoms. How repeat instability is mediated by DNA replication, repair, recombination, transcription and epigenetics may explain its contribution to pathogenesis and give insights into therapeutic strategies to block expansions or induce contractions.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Expanded tandem DNA repeats have been linked to more than 40 single-gene disorders.
“When expanded, they have been associated with >40 monogenic disorders1.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [1]
Disease-causing, functionally impactful tandem repeat expansions tend to be large and rare in the general population.
“Tandem repeat expansions that are disease-causing and functionally impactful tend to be large and rare in the general population1,38.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [1]
The transmission expansion bias of longer repeats matches instability trends for almost all disease-associated tandem repeats.
“This transmission expansion bias of longer tandem repeats is consistent with the instability trends for almost every disease-associated tandem repeat1,38.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [1]
Cites
Expandable DNA repeats and human disease
Mirkin, S. M. (2007) · Nature · doi:10.1038/nature05977 · Cited by 934 · see citing works
Repeat instability: mechanisms of dynamic mutations
Pearson, C. E., Edamura, K. N., & Cleary, J. D. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1689 · Cited by 924 · cited 1× · see citing works
“Trinucleotide repeats (TNRs), which include CAG, CTG, CGG and GAA triplets, are the most common unstable disease-associated DNA repeats, but tetranucleotides, pentanucleotides, minisatellites and megasatellites are also involved in causing diseas”
BackgroundRepeat instability : mechanisms of dynamic mutations
Pearson, C. E. (2005) · Medical Entomology and Zoology · Cited by 711 · see citing works
Self-citationUnstable Tandem Repeats in Promoters Confer Transcriptional Evolvability
Vinces, M. D., Legendre, M., Caldara, M., Hagihara, M., & Verstrepen, K. J. (2009) · Science · doi:10.1126/science.1170097 · Cited by 372 · see citing works
Swami, M., Hendricks, A. E., Gillis, T., Massood, T., Mysore, J. S., Myers, R. H., & Wheeler, V. C. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp242 · Cited by 330 · see citing works
Eiges, R., Urbach, A., Malcov, M., Frumkin, T., Schwartz, T., Amit, A., Yaron, Y., Eden, A., Yanuka, O., Benvenisty, N., et al. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.09.001 · Cited by 287 · see citing works
Al‐Mahdawi, S., Pinto, R. M., Ismail, O., Varshney, D., Lymperi, S., Sandi, C., Trabzuni, D., & Pook, M. A. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm346 · Cited by 254 · see citing works
Ladd, P. D., Smith, L. E., Rabaia, N. A., Moore, J. M., Georges, S. A., Hansen, R. S., Hagerman, R. J., Tassone, F., Tapscott, S. J., & Filippova, G. N. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm293 · Cited by 248 · see citing works
DNA instability in postmitotic neurons
Gonitel, R., Moffitt, H., Sathasivam, K., Woodman, B., Detloff, P., Faull, R., & Bates, G. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0800048105 · Cited by 225 · see citing works
(CAG)n-hairpin DNA binds to Msh2–Msh3 and changes properties of mismatch recognition
Owen, B. A. L., Yang, Z., Lai, M., Gajek, M., Badger, J. D., Hayes, J. J., Edelmann, W., Kucherlapati, R., Wilson, T., & McMurray, C. T. (2005) · Nature Structural & Molecular Biology · doi:10.1038/nsmb965 · Cited by 222 · see citing works
R loops stimulate genetic instability of CTG·CAG repeats
Lin, Y., Dent, S., Wilson, J. H., Wells, R. D., & Напиерала, М. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909740107 · Cited by 193 · see citing works
Entezam, A., Biacsi, R. E., Orrison, B. M., Saha, T., Hoffman, G. E., Grabczyk, E., Nussbaum, R. L., & Usdin, K. (2007) · Gene · doi:10.1016/j.gene.2007.02.026 · Cited by 184 · see citing works
Expanded Repeat in Canine Epilepsy
Lohi, H., Young, E. J., Fitzmaurice, S. N., Rusbridge, C., Chan, E. M., Vervoort, M., Turnbull, J., Zhao, X.-C., Ianzano, L., Paterson, A. D., et al. (2005) · Science · doi:10.1126/science.1102832 · Cited by 170 · see citing works
Transcription promotes contraction of CAG repeat tracts in human cells
Lin, Y., Dion, V., & Wilson, J. H. (2006) · Nature Structural &Molecular Biology · doi:10.1038/nsmb1042 · Cited by 169 · see citing works
Slipped (CTG)•(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair
Panigrahi, G., Lau, R., Montgomery, S., Leonard, M. R., & Pearson, C. E. (2005) · Nature Structural &Molecular Biology · doi:10.1038/nsmb959 · Cited by 159 · see citing works
Self-citationHighly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene
Mušová, Z., Mazanec, R., Křepelová, A., Ehler, E., Vales, J., Jaklova, R., Procházka, T., Koukal, P., Maříková, T., Kraus, J., et al. (2009) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.32987 · Cited by 157 · see citing works
Braida, C., Stefanatos, R. K. A., Adam, B., Mahajan, N., Smeets, H. J. M., Niel, F., Goizet, C., Arveiler, B., Koenig, M., Lagier‐Tourenne, C., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq015 · Cited by 157 · see citing works
Foiry, L., Dong, L., Savouret, C., Hubert, L., Riele, H. T., Junien, C., & Gourdon, G. (2006) · Human Genetics · doi:10.1007/s00439-006-0164-7 · Cited by 151 · see citing works
Goula, A.-V., Berquist, B. R., Wilson, D. M., Wheeler, V. C., Trottier, Y., & Mérienne, K. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000749 · Cited by 145 · see citing works
Grabczyk, E., Mancuso, M. M., & Sammarco, M. C. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm589 · Cited by 145 · see citing works
Large-scale expansions of Friedreich’s ataxia GAA repeats in yeast
Shishkin, A. A., Voineagu, I., Matera, R., Cherng, N., Chernet, B. T., Krasilnikova, M., Narayanan, V., Lobachev, K., & Mirkin, S. (2009) · Molecules and Cells · doi:10.1016/j.molcel.2009.06.017 · Cited by 143 · see citing works
Libby, R. T., Hagerman, K. A., Pineda, V. V., Lau, R., Cho, D. H., Baccam, S. L., Axford, M. M., Cleary, J. D., Moore, J. M., Sopher, B. L., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000257 · Cited by 138 · see citing works
Self-citationCleary, J. D., & Pearson, C. E. (2003) · Cytogenetic and Genome Research · doi:10.1159/000072837 · Cited by 138 · see citing works
Self-citationCREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease
Jung, J., & Bonini, N. M. (2007) · Science · doi:10.1126/science.1139517 · Cited by 133 · see citing works
Coordination between Polymerase β and FEN1 Can Modulate CAG Repeat Expansion
Liu, Y., Prasad, R., Beard, W. A., Hou, E. W., Horton, J. K., McMurray, C. T., & Wilson, S. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.050286 · Cited by 115 · see citing works
Castaldo, I., Pinelli, M., Monticelli, A., Acquaviva, F., Giacchetti, M., Filla, A., Sacchetti, S., Keller, S., Avvedimento, V. E., Chiariotti, L., et al. (2008) · Journal of Medical Genetics · doi:10.1136/jmg.2008.058594 · Cited by 112 · see citing works
CTG Trinucleotide Repeat “Big Jumps”: Large Expansions, Small Mice
Gomes-Pereira, M., Foiry, L., Nicole, A., Huguet-Lachon, A., Junien, C., Münnich, A., & Gourdon, G. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030052 · Cited by 109 · see citing works
MSH2 ATPase Domain Mutation Affects CTG•CAG Repeat Instability in Transgenic Mice
Tomé, S., Holt, I., Edelmann, W., Morris, G. E., Münnich, A., Pearson, C. E., & Gourdon, G. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000482 · Cited by 103 · see citing works
Self-citationSRS2 and SGS1 prevent chromosomal breaks and stabilize triplet repeats by restraining recombination
Kerrest, A., Anand, R. P., Sundararajan, R., Bermejo, R., Liberi, G., Dujon, B., Freudenreich, C., & Richard, G.-F. (2009) · Nature Structural &Molecular Biology · doi:10.1038/nsmb.1544 · Cited by 97 · see citing works
Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline
Dion, V., Lin, Y., Hubert, L., Waterland, R. A., & Wilson, J. H. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn019 · Cited by 95 · see citing works
Mittelman, D., Moye, C., Morton, J. J., Sykoudis, K., Lin, Y., Carroll, D., & Wilson, J. H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902420106 · Cited by 94 · see citing works
A Genetic Defect Caused by a Triplet Repeat Expansion in Arabidopsis thaliana
Sureshkumar, S., Todesco, M., Schneeberger, K., Harilal, R., Balasubramanian, S., & Weigel, D. (2009) · Science · doi:10.1126/science.1164014 · Cited by 93 · see citing works
Yang, Z., Lau, R., Marcadier, J. L., Chitayat, D. A., & Pearson, C. E. (2003) · The American Journal of Human Genetics · doi:10.1086/379523 · Cited by 86 · see citing works
Self-citationSlipping while sleeping? Trinucleotide repeat expansions in germ cells
Pearson, C. E. (2003) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2003.09.006 · Cited by 79 · see citing works
Self-citationHuman embryonic stem cell models of Huntington disease
Niclis, J. C., Trounson, A. O., Dottori, M., Ellisdon, A. M., Bottomley, S., Verlinsky, Y., & Cram, D. (2009) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)60053-3 · Cited by 74 · see citing works
Structure-Dependent DNA Damage and Repair in a Trinucleotide Repeat Sequence
Jarem, D. A., Wilson, N. R., & Delaney, S. (2009) · Biochemistry · doi:10.1021/bi9007403 · Cited by 71 · see citing works
Gomes-Pereira, M. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh612 · Cited by 66 · see citing works
Chromatin Remodeling in the Noncoding Repeat Expansion Diseases
Kumari, D., & Usdin, K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.r800026200 · Cited by 63 · see citing works
Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients
Hashem, V. I. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh976 · Cited by 60 · see citing works
Slean, M. M., Panigrahi, G. B., Ranum, L. P. W., & Pearson, C. E. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.03.014 · Cited by 53 · see citing works
Self-citationMismatch Recognition Protein MutSβ Does Not Hijack (CAG) Hairpin Repair in Vitro
Tian, L., Hou, C., Tian, K., Holcomb, N., Gu, L., & Li, G. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.c109.014977 · Cited by 52 · see citing works
Incision-dependent and error-free repair of (CAG)n/(CTG)n hairpins in human cell extracts
Hou, C., Chan, N. L. S., Gu, L., & Li, G. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1638 · Cited by 52 · see citing works
Checkpoint responses to unusual structures formed by DNA repeats
Voineagu, I., Freudenreich, C. H., & Mirkin, S. M. (2009) · Molecular Carcinogenesis · doi:10.1002/mc.20512 · Cited by 48 · see citing works
López, A., Tomkinson, A. E., & Pearson, C. E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.034405 · Cited by 43 · see citing works
Self-citationMrc1, Tof1 and Csm3 inhibit CAG·CTG repeat instability by at least two mechanisms
Razidlo, D. F., & Lahue, R. S. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.01.009 · Cited by 42 · see citing works
Edwards, S. F., Sirito, M., Krahe, R., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807699106 · Cited by 38 · see citing works
Entezam, A., & Usdin, K. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp666 · Cited by 34 · see citing works
Rapid unwinding of triplet repeat hairpins by Srs2 helicase of Saccharomyces cerevisiae
Dhar, A., & Lahue, R. S. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn225 · Cited by 33 · see citing works
Temmerman, N. D., Seneca, S., Steirteghem, A. V., Haentjens, P., Elst, J. V. D., Liebaers, I., & Sermon, K. (2008) · Molecular Human Reproduction · doi:10.1093/molehr/gan034 · Cited by 28 · see citing works
Huntingtin triplet-repeat locus is stable under long-term Fen1 knockdown in human cells
Moe, S. E., Sorbo, J. G., & Holen, T. (2008) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2008.03.012 · Cited by 22 · see citing works
SCA8 CAG/CTG Expansions, a Tale of Two TOXICities: A Unique or Common Case?
Mérienne, K., & Trottier, Y. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000593 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Maintaining genome stability at the replication fork
Branzei, D., & Foiani, M. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2852 · Cited by 786 · see citing works
Tandem repeats mediating genetic plasticity in health and disease
Hannan, A. J. (2018) · Nature Reviews Genetics · doi:10.1038/nrg.2017.115 · Cited by 446 · see citing works
Molecular mechanisms underlying nucleotide repeat expansion disorders
Malik, I., Kelley, C. P., Wang, E. T., & Todd, P. K. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00382-6 · Cited by 363 · see citing works
Genome-wide detection of tandem DNA repeats that are expanded in autism
Trost, B., Engchuan, W., Nguyen, C. M., Thiruvahindrapuram, B., Dolzhenko, E., Backstrom, I., Mirceta, M., Mojarad, B. A., Yin, Y., Dov, A., et al. (2020) · Nature · doi:10.1038/s41586-020-2579-z · Cited by 238 · see citing works
Self-citationDNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases
Bettencourt, C., Hensman‐Moss, D., Flower, M., Wiethoff, S., Brice, A., Goizet, C., Stevanin, G., Koutsis, G., Karadima, G., Panas, M., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24656 · Cited by 227 · see citing works
DNA replication fidelity and cancer
Preston, B. D., Albertson, T. M., & Herr, A. J. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.10.009 · Cited by 160 · see citing works
DNA triplet repeat expansion and mismatch repair
Iyer, R. R., Pluciennik, A., Napierala, M., & Wells, R. D. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-034010 · Cited by 130 · see citing works
Involvement of long noncoding RNAs in diseases affecting the central nervous system
Pastori, C., & Wahlestedt, C. (2012) · RNA Biology · doi:10.4161/rna.20482 · Cited by 100 · see citing works
- Authors
- López Castel, A., Cleary, J. D., & Pearson, C. E.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Pearson, Christopher E.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2010-03
- Volume
- 11
- Issue
- 3
- Pages
- 165-170
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- OpenAlex
- W2037606715
- Cited by
- 429
- References
- 51
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 15 · 2023: 10 · 2022: 21 · 2021: 24 · 2020: 33 · 2019: 27 · 2018: 25 · 2017: 21 · 2016: 32 · 2015: 33 · 2014: 27 · 2013: 52 · 2012: 42
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Rochester
- Muscular Dystrophy Canada
- Hospital for Sick Children
- National Institutes of Health (5u54ns048843-12)
- Canadian Institutes of Health Research
- National Institute of Neurological Disorders and Stroke (U54NS48843)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- repeat instability, repetitive DNA, trinucleotide repeat expansion, repeat contraction, neurological disorders, neuromuscular disorders, DNA replication, DNA repair, recombination, transcription, epigenetics, therapeutic target, repeat length
- MeSH terms
- Animals, Base Sequence, DNA Damage, DNA Repair, DNA Replication, Drug Therapy, Humans, Models, Biological, Transcription, Genetic, Trinucleotide Repeats, Trinucleotide Repeat Expansion, Genetic Predisposition to Disease, Genomic Instability, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
