Cited by 926Genetic Neurodegenerative DiseasesGenetic factors in colorectal cancerDNA Repair Mechanisms

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Repeat instability: mechanisms of dynamic mutations

Pearson, Christopher E., Edamura, Kerrie Nichol, Cleary, John D.·2005·Nature Reviews Genetics

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Abstract

Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.

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“stages of disease progression (UHDRS total functional capacity range 3–13 and motor score range 30–52) revealed marked deficits in psycho-motor speed dexterity and visuoconstructive ability, which presented very early in the disease 90 .”
Modeling Human Trinucleotide Repeat Diseases in Drosophila
Yu, Z., & Bonini, N. M. (2011) · International review of neurobiology · doi:10.1016/b978-0-12-387003-2.00008-2 · Cited by 18
“A number of the microsatellite sequences, with trinucleotide repeats being the most common, can undergo dynamic expansion and lead to human neurological diseases (Mirkin, 2007; Pearson et al., 2005).”
Background
Identification of restriction endonucleases sensitive to 5-cytosine methylation at non-CpG sites, including expanded (CAG)n/(CTG)n repeats
López, A., Nakamori, M., Thornton, C. A., & Pearson, C. E. (2011) · Epigenetics · doi:10.4161/epi.6.4.14953 · Cited by 17
“For myotonic dystrophy (DM1), Friedreich’s ataxia (FRDA) and Huntington disease (HD) involving the non-CpG repeat motifs (CTG)n, (GAA)n and (CAG)n, respectively, acquisition of CpG methylation profiles has been observed adjacent to the mutated repeat alleles.(2,5-11) Most studies of DNA methylation assess 5'-CpG-3' bu…”
Background
Polyglutamine expansion in Drosophila: thermal stress and Hsp70 as selective agents
Bettencourt, B. R., Hogan, C. C., & Nimali, M. (2007) · Journal of Biosciences · doi:10.1007/s12038-007-0053-9 · Cited by 18
“These repeats are prone to expansion due to polymerase slippage, caused by secondary structure formation within the repeats themselves (Pearson et al 2005).”
Background
A Novel Electrochemical Biosensor Based on a Double-Signal Technique for d(CAG)n Trinucleotide Repeats
Li, J., Liu, Y., Zhu, X., Chang, G., He, H., Zhang, X., & Wang, S. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b15014 · Cited by 17
Absence of AGG Interruptions Is a Risk Factor for Full Mutation Expansion Among Israeli FMR1 Premutation Carriers
Domniz, N., Ries‐Levavi, L., Cohen, Y., Haham, L. M., Berkenstadt, M., Pras, E., Glicksman, A., Tortora, N. D., Latham, G. J., Hadd, A. G., et al. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00606 · Cited by 16
A Computational Framework Discovers New Copy Number Variants with Functional Importance
Banerjee, S., Oldridge, D. A., Poptsova, M. S., Hussain, W. M., Chakravarty, D., & Demichelis, F. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017539 · Cited by 17
“Non Homologous Recombination (NHR) constitutes the major part of all CNV formation mechanisms (69.21%), while Transposable Element Insertion (TEI) and Variable Number of Tandem Repeat (VNTR) take up 20.84% and 6.27%, respectively. Non-allelic homologous recombination (NAHR) events constitute 3.68% of all CNV mechanism…”
BackgroundInfluential
The ATTCT repeats of spinocerebellar ataxia type 10 display strong nucleosome assembly which is enhanced by repeat interruptions
Hagerman, K. A., Ruan, H., Edamura, K. N., Matsuura, T., Pearson, C. E., & Wang, Y. (2008) · Gene · doi:10.1016/j.gene.2008.12.011 · Cited by 18
“The expansion of repeat tracts is associated with at least 42 human diseases (Cleary and Pearson, 2003; Pearson et al., 2005).”
Background
Impact of bulge loop size on DNA triplet repeat domains: Implications for DNA repair and expansion
Völker, J., Plum, G., Gindikin, V. S., KLUMP, H. H., & Breslauer, K. J. (2013) · Biopolymers · doi:10.1002/bip.22236 · Cited by 16
Modeling simple repeat expansion diseases with iPSC technology
Jaworska, E., Kozłowska, E., Switonski, P. M., & Krzyżosiak, W. J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2284-0 · Cited by 17
“Third, there is a correlation between the number of repeats and both the age of disease onset and the severity of the symptoms [50].”
Background
Reverse Transcription Errors and RNA–DNA Differences at Short Tandem Repeats
Fungtammasan, A., Tomaszkiewicz, M., Campos-Sánchez, R., Eckert, K. A., DeGiorgio, M., & Makova, K. D. (2016) · Molecular Biology and Evolution · doi:10.1093/molbev/msw139 · Cited by 16
“They are particularly important for understanding disease susceptibility, as mutations at STRs are implicated in over 40 neurological disorders (Boby et al. 2005; Pearson et al. 2005; Castel et al. 2010), and, more than 30% of human genes contain one or more STRs in their exonic regions (Legendre et al.”
Background
Centromere: A Trojan horse for genome stability
Scelfo, A., & Fachinetti, D. (2023) · DNA repair · doi:10.1016/j.dnarep.2023.103569 · Cited by 16
Insights into medicinal attributes of imidazo[1,2‐a]pyridine derivatives as anticancer agents
Kumar, A., Sharma, V., Behl, T., Ganesan, S., Nathiya, D., Gulati, M., Khalid, M., Elossaily, G. M., Chigurupati, S., & Sachdeva, M. (2024) · Archiv der Pharmazie · doi:10.1002/ardp.202400402 · Cited by 16
Microsatellite-encoded domain in rodent Sry functions as a genetic capacitor to enable the rapid evolution of biological novelty
Chen, Y., Racca, J. D., Sequeira, P. W., Phillips, N. B., & Weiss, M. A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300860110 · Cited by 18
Congenital myotonic dystrophy: ventriculomegaly and shunt considerations for the pediatric neurosurgeon
Mutchnick, I. S., Thatikunta, M., Gump, W. C., Stewart, D. L., & Moriarty, T. M. (2016) · Child s Nervous System · doi:10.1007/s00381-015-2993-y · Cited by 16
“Germline repeat length instability and the process leading to somatic mosaicism are unclear [12].”
Background
A microsatellite repeat in PCA3 long non-coding RNA is associated with prostate cancer risk and aggressiveness
Lai, J., Moya, L., An, J., Hoffman, A., Srinivasan, S., Panchadsaram, J., Walpole, C., Perry‐Keene, J., Chambers, S. K., BioResource, A. P. C., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-16700-y · Cited by 16
In- silico exploration of thirty alphavirus genomes for analysis of the simple sequence repeats
Alam, C. M., Singh, A. K., Sharfuddin, C., & Ali, S. (2014) · Meta Gene · doi:10.1016/j.mgene.2014.09.005 · Cited by 16
“For instance, more the number of repeats; higher is the mutability (Pearson et al., 2005).”
Background
Abnormal Base Excision Repair at Trinucleotide Repeats Associated with Diseases: A Tissue-Selective Mechanism
Goula, A.-V., & Mérienne, K. (2013) · Genes · doi:10.3390/genes4030375 · Cited by 19
“In most TNR diseases, the degree of variation of the repeat tract over time is highly dependent upon tissue or cell-type, and the tissues or cells presenting high TNR instability vary to some extent between diseases [2].”
Background
Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination
Dion, V., Lin, Y., Price, B. A., Fyffe-Maricich, S. L., Seluanov, A., Gorbunova, V. A., & Wilson, J. H. (2008) · DNA repair · doi:10.1016/j.dnarep.2007.11.002 · Cited by 16
“Expanded tracts of trinucleotide repeats cause at least 18 human diseases [1,2].”
Background
Buried territories: heterochromatic response to DNA double-strand breaks
Feng, Y.-L., Xiang, J.-F., Kong, N., Cai, X., & Xie, A. (2016) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmw033 · Cited by 16
“These repair mechanisms can induce deletions, translocations, and other chromosomal rearrangements, thus causing instability in heterochromatic domains in chromosomes [122,123].”
Background
Bicyclic and tricyclic C–C mismatch-binding ligands bind to CCG trinucleotide repeat DNAs
Shibata, T., & Nakatani, K. (2018) · Chemical Communications · doi:10.1039/c8cc02393j · Cited by 16
Central auditory processing in patients with spinocerebellar ataxia
Zeigelboim, B. S., de Carvalho, H. A. S., Teive, H. A. G., Liberalesso, P. B. N., Jurkiewicz, A. L., Abdulmassih, E. M. D. S., Marques, J. M., & Cordeiro, M. L. (2015) · Hearing Research · doi:10.1016/j.heares.2015.07.006 · Cited by 17
“Nearly a third of our participants exhibited signs of hearing loss, with those in the SCA3 and SCA10 subgroups having abnormal audiological results more frequently than those in the SCA2 subgroup.”
Influential
Coherent states as consequences of keto‐amino→ enol‐imine hydrogen bond arrangements driven by quantum uncertainty limits on amino DNA protons
Cooper, W. G. (2012) · International Journal of Quantum Chemistry · doi:10.1002/qua.22834 · Cited by 16
Minimal prevalence of Huntington’s disease in the South of Brazil and instability of the expanded CAG tract during intergenerational transmissions
Castilhos, R. M., dos Santos, J. A., Augustin, M. C., Pedroso, J. L., Barsottini, O. G. P., Saba, R. A., Ferraz, H. B., Godeiro-Junior, C. D. O., Vargas, F. R., Salarini, D. Z., et al. (2019) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2018-0032 · Cited by 14
“Instabilities in maternal CAG repeat transmissions might be related to DNA repair errors related to the protracted meiosis (Pearson et al., 2005; Mirkin 2007).”
Background
Novel eGZ-motif formed by regularly extruded guanine bases in a left-handed Z-DNA helix as a major motif behind CGG trinucleotide repeats
Fakharzadeh, A., Zhang, J., Roland, C., & Sagui, C. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac339 · Cited by 15
G-Quadruplexes in Repeat Expansion Disorders
Teng, Y., Zhu, M. L., & Qiu, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032375 · Cited by 16
Epigenetic modifications in human fragile X pluripotent stem cells; Implications in fragile X syndrome modeling
Gerhardt, J. (2015) · Brain Research · doi:10.1016/j.brainres.2015.10.004 · Cited by 15
Sample enrichment for clinical trials to show delay of onset in huntington disease
Paulsen, J. S., Lourens, S. G., Kieburtz, K. D., & Zhang, Y. (2019) · Movement Disorders · doi:10.1002/mds.27595 · Cited by 15
“Despite widespread usage, age of HD onset is not completely explained by CAG repeat length.(22-28) Figure 1(29) confirms wide onset age variation for individuals with the same CAG repeat length.”
Background
Development of novel macrocyclic small molecules that target CTG trinucleotide repeats
Serrano, J. F., Lee, J., Curet, L. D., Hagler, L. D., Krueger, S. B., Schuster, E. J., & Zimmerman, S. C. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.05.022 · Cited by 15
De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis
Arai, H., Otagiri, T., Sasaki, A., Hashimoto, T., Umetsu, K., Tokunaga, K., & Hayasaka, K. (2007) · Journal of Human Genetics · doi:10.1007/s10038-007-0197-3 · Cited by 15
Copy-number variation analysis in familial nonsyndromic congenital anomalies of the kidney and urinary tract: Evidence for the causative role of a transposable element-associated genomic rearrangement
Siomou, E. C., Mitsioni, A. G., Giapros, V. I., Bouba, I., Noutsopoulos, D., & Georgiou, I. A. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6462 · Cited by 14
“Given that TEs can form non B-DNA structures promoting the formation of DNA nicks, double strand breaks or stall replication forks (26), we cannot exclude the involvement of microhomology-mediated replication-dependent recombination mechanisms, as previously reported in human Xq isochromosome…”
Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases
Barbé, L., & Finkbeiner, S. M. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.750629 · Cited by 15
Frustration Between Preferred States of Complementary Trinucleotide Repeat DNA Hairpins Anticorrelates with Expansion Disease Propensity
Xu, P., Zhang, J., Pan, F., Mahn, C., Roland, C., Sagui, C., & Weninger, K. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168086 · Cited by 14
Anticipation in familial hematologic malignancies
Tegg, E. M., Thomson, R. J., Stankovich, J. M., Banks, A., MARSDEN, K. A., Lowenthal, R. M., Foote, S. J., & Dickinson, J. L. (2010) · Blood · doi:10.1182/blood-2010-07-296475 · Cited by 14
Modulating RNA secondary and tertiary structures by mismatch binding ligands
Murata, A., Nakamori, M., & Nakatani, K. (2019) · Methods · doi:10.1016/j.ymeth.2019.05.006 · Cited by 17
Compensatory relationship between low-complexity regions and gene paralogy in the evolution of prokaryotes
Persi, E., Wolf, Y. I., Karamycheva, S. A., Makarova, K. S., & Koonin, E. V. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2300154120 · Cited by 13
Mismatch repair enhances convergent transcription-induced cell death at trinucleotide repeats by activating ATR
Chatterjee, N., Lin, Y., & Wilson, J. H. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.03.016 · Cited by 13
The SSV Evaluation System: A Tool to Prioritize Short Structural Variants for Studies of Possible Regulatory and Causal Variants
Saul, R., Lutz, M. W., Burns, D. K., Roses, A. D., & Chiba‐Falek, O. (2016) · Human Mutation · doi:10.1002/humu.23023 · Cited by 15
“Recently, there has been increased support for the idea that SSVs may contribute to variation in gene expression in humans and also contribute to many human complex traits [Pearson et al., 2005; Mirkin, 2007; Willems et al., 2014; Gymrek et al., 2016].”
Background
Cyclic mismatch binding ligand CMBL4 binds to the 5′-T-3′/5′-GG-3′ site by inducing the flipping out of thymine base
Mukherjee, S., Dohno, C., Asano, K., & Nakatani, K. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw672 · Cited by 14
Length polymorphism and head shape association among genes with polyglutamine repeats in the stalk-eyed fly, Teleopsis dalmanni
Birge, L. M., Pitts, M. L., Baker, R. H., & Wilkinson, G. S. (2010) · BMC Evolutionary Biology · doi:10.1186/1471-2148-10-227 · Cited by 14
“This proposition is based on the observation that trinucleotide repeats are common in eukaryotic DNA [19-21] and undergo mutation as a consequence of replication slippage more frequently than amino acid substitutions [11,22] but see [23].”
Background
Human Nucleotide Expansion Disorders
Fry, M., & Usdin, K. (2006) · Springer eBooks · doi:10.1007/3-540-33336-3 · Cited by 14
Genetic instabilities of (CCTG)·(CAGG) and (ATTCT)·(AGAAT) disease‐associated repeats reveal multiple pathways for repeat deletion
Edwards, S. F., Hashem, V. I., Klysik, E. A., & Sinden, R. R. (2009) · Molecular Carcinogenesis · doi:10.1002/mc.20534 · Cited by 16
Modification of Huntington’s disease by short tandem repeats
Hong, E. P., Ramos, E. M., Aziz, N. A., Massey, T. H., McAllister, B., Lobanov, S. V., Jones, L., Holmans, P., Kwak, S., Orth, M., et al. (2024) · Brain Communications · doi:10.1093/braincomms/fcae016 · Cited by 13
Low-input PacBio sequencing generates high-quality individual fly genomes and characterizes mutational processes
Jia, H., Tan, S., Cai, Y., Guo, Y., Shen, J., Zhang, Y., Ma, H., Zhang, Q., Chen, J., Qiao, G., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49992-6 · Cited by 13
Role of senataxin in R-loop-mediated neurodegeneration
Kannan, A., Leela, S. G., Branzei, D., & Gangwani, L. (2024) · Brain Communications · doi:10.1093/braincomms/fcae239 · Cited by 14
“51,52 R-loops formed following transcription of GC-rich trinucleo-tide repeats become highly stable due to the formation of G4 and triplex DNA structures in the non-transcribing DNA strand, which further stabilize the R-loops and increase the probability for DNA damage and genomic instability.”
Background

Authors: Pearson, C. E., Edamura, K. N., & Cleary, J. D.
Affiliations: University of Toronto (CA)
Hospital for Sick Children (CA)
Corresponding author: Pearson, Christopher E.
ORCID: Pearson, Christopher E.
Venue: Nature Reviews Genetics
Publisher: Springer Science and Business Media LLC
Published: 2005-10
Volume: 6
Issue: 10
Pages: 729-742
ISSN: 1471-0056 (ISSN-L)
1471-0064
DOI: 10.1038/nrg1689
OpenAlex: W2087505473
Cited by: 924
References: 157
Citations by year: 2026: 13 · 2025: 23 · 2024: 45 · 2023: 29 · 2022: 25 · 2021: 54 · 2020: 27 · 2019: 38 · 2018: 53 · 2017: 45 · 2016: 58 · 2015: 41 · 2014: 55 · 2013: 46 · 2012: 56
FWCI: 3.89
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Genetics (publishedVersion)
PubMed (publishedVersion)
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 › Molecular Biology › DNA Repair Mechanisms
Keywords: repeat instability, dynamic mutation, trinucleotide repeat disorders, neurodegenerative diseases, neuromuscular disorders, cis-regulatory elements, trans-acting proteins, DNA replication, DNA repair, DNA recombination, DNA secondary structure
MeSH terms: DNA Repair, DNA Replication, Humans, Models, Genetic, Mutation, Recombination, Genetic, Trinucleotide Repeat Expansion, Heredodegenerative Disorders, Nervous System, DNA Repeat Expansion, Genomic Instability

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Repeat instability: mechanisms of dynamic mutations

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