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Journal articles on the topic 'Repeat instabilty'

Author: Grafiati

Published: 19 October 2024

Last updated: 31 July 2025

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1

Khristich, Alexandra N., and Sergei M. Mirkin. "On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability." Journal of Biological Chemistry 295, no. 13 (2020): 4134–70. http://dx.doi.org/10.1074/jbc.rev119.007678.

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the

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2

Lin, Yunfu, and John H. Wilson. "Transcription-Induced CAG Repeat Contraction in Human Cells Is Mediated in Part by Transcription-Coupled Nucleotide Excision Repair." Molecular and Cellular Biology 27, no. 17 (2007): 6209–17. http://dx.doi.org/10.1128/mcb.00739-07.

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ABSTRACT Expansions of CAG repeat tracts in the germ line underlie several neurological diseases. In human patients and mouse models, CAG repeat tracts display an ongoing instability in neurons, which may exacerbate disease symptoms. It is unclear how repeats are destabilized in nondividing cells, but it cannot involve DNA replication. We showed previously that transcription through CAG repeats induces their instability (Y. Lin, V. Dion, and J. H. Wilson, Nat. Struct. Mol. Biol. 13:179-180). Here, we present a genetic analysis of the link between transcription-induced repeat instability and nu

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3

Cohen, Haim, Dorothy D. Sears, Drora Zenvirth, Philip Hieter, and Giora Simchen. "Increased Instability of Human CTG Repeat Tracts on Yeast Artificial Chromosomes during Gametogenesis." Molecular and Cellular Biology 19, no. 6 (1999): 4153–58. http://dx.doi.org/10.1128/mcb.19.6.4153.

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ABSTRACT Expansion of trinucleotide repeat tracts has been shown to be associated with numerous human diseases. The mechanism and timing of the expansion events are poorly understood, however. We show that CTG repeats, associated with the human DMPK gene and implanted in two homologous yeast artificial chromosomes (YACs), are very unstable. The instability is 6 to 10 times more pronounced in meiosis than during mitotic division. The influence of meiosis on instability is 4.4 times greater when the second YAC with a repeat tract is not present. Most of the changes we observed in trinucleotide r

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4

Brouwer, Judith Rixt, Aline Huguet, Annie Nicole, Arnold Munnich, and Geneviève Gourdon. "Transcriptionally Repressive Chromatin Remodelling and CpG Methylation in the Presence of Expanded CTG-Repeats at the DM1 Locus." Journal of Nucleic Acids 2013 (2013): 1–16. http://dx.doi.org/10.1155/2013/567435.

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An expanded CTG-repeat in the 3′ UTR of theDMPKgene is responsible for myotonic dystrophy type I (DM1). Somatic and intergenerational instability cause the disease to become more severe during life and in subsequent generations. Evidence is accumulating that trinucleotide repeat instability and disease progression involve aberrant chromatin dynamics. We explored the chromatin environment in relation to expanded CTG-repeat tracts in hearts from transgenic mice carrying the DM1 locus with different repeat lengths. Using bisulfite sequencing we detected abundant CpG methylation in the regions fla

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5

Gold, Michaela A., Jenna M. Whalen, Karine Freon, et al. "Restarted replication forks are error-prone and cause CAG repeat expansions and contractions." PLOS Genetics 17, no. 10 (2021): e1009863. http://dx.doi.org/10.1371/journal.pgen.1009863.

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Disease-associated trinucleotide repeats form secondary DNA structures that interfere with replication and repair. Replication has been implicated as a mechanism that can cause repeat expansions and contractions. However, because structure-forming repeats are also replication barriers, it has been unclear whether the instability occurs due to slippage during normal replication progression through the repeat, slippage or misalignment at a replication stall caused by the repeat, or during subsequent replication of the repeat by a restarted fork that has altered properties. In this study, we have

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Neil, Alexander J., Julia A. Hisey, Ishtiaque Quasem, et al. "Replication-independent instability of Friedreich’s ataxia GAA repeats during chronological aging." Proceedings of the National Academy of Sciences 118, no. 5 (2021): e2013080118. http://dx.doi.org/10.1073/pnas.2013080118.

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Nearly 50 hereditary diseases result from the inheritance of abnormally long repetitive DNA microsatellites. While it was originally believed that the size of inherited repeats is the key factor in disease development, it has become clear that somatic instability of these repeats throughout an individual’s lifetime strongly contributes to disease onset and progression. Importantly, somatic instability is commonly observed in terminally differentiated, postmitotic cells, such as neurons. To unravel the mechanisms of repeat instability in nondividing cells, we created an experimental system to a

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7

Calluori, Stephanie, Rebecca Stark, and Brandon L. Pearson. "Gene–Environment Interactions in Repeat Expansion Diseases: Mechanisms of Environmentally Induced Repeat Instability." Biomedicines 11, no. 2 (2023): 515. http://dx.doi.org/10.3390/biomedicines11020515.

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Short tandem repeats (STRs) are units of 1–6 base pairs that occur in tandem repetition to form a repeat tract. STRs exhibit repeat instability, which generates expansions or contractions of the repeat tract. Over 50 diseases, primarily affecting the central nervous system and muscles, are characterized by repeat instability. Longer repeat tracts are typically associated with earlier age of onset and increased disease severity. Environmental exposures are suspected to play a role in the pathogenesis of repeat expansion diseases. Here, we review the current knowledge of mechanisms of environmen

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8

Gorbunova, Vera, Andrei Seluanov, Vincent Dion, Zoltan Sandor, James L. Meservy, and John H. Wilson. "Selectable System for Monitoring the Instability of CTG/CAG Triplet Repeats in Mammalian Cells." Molecular and Cellular Biology 23, no. 13 (2003): 4485–93. http://dx.doi.org/10.1128/mcb.23.13.4485-4493.2003.

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ABSTRACT Despite substantial progress in understanding the mechanism by which expanded CTG/CAG trinucleotide repeats cause neurodegenerative diseases, little is known about the basis for repeat instability itself. By taking advantage of a novel phenomenon, we have developed a selectable assay to detect contractions of CTG/CAG triplets. When inserted into an intron in the APRT gene or the HPRT minigene, long tracts of CTG/CAG repeats (more than about 33 repeat units) are efficiently incorporated into mRNA as a new exon, thereby rendering the encoded protein nonfunctional, whereas short repeat t

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9

Jung, Da Eun, and Chul Hyoung Lyoo. "A Spinocerebellar Ataxia Type 6 Patient Caused by <i>De Novo</i> Expansion of Normal Range CAG Repeats." Journal of the Korean Neurological Association 42, no. 2 (2024): 150–52. http://dx.doi.org/10.17340/jkna.2023.0105.

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Spinocerebellar ataxia type 6 (SCA6) is classified as a CAG repeat disorder, where the number of expanded CAG repeats often undergoes meiotic instability, when transmitted from one generation to the next. However, in SCA6, both normal and expanded CAG repeats tend to remain stable during transmission due to its relatively small repeat numbers. We herein report <i>de-novo</i> expansion of CAG repeats in SCA6 gene in a 41-year-old female patient, whose parents had normal repeat numbers.

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10

Su, Xiaofeng A., and Catherine H. Freudenreich. "Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae." Proceedings of the National Academy of Sciences 114, no. 40 (2017): E8392—E8401. http://dx.doi.org/10.1073/pnas.1711283114.

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CAG/CTG repeats are structure-forming repetitive DNA sequences, and expansion beyond a threshold of ∼35 CAG repeats is the cause of several human diseases. Expanded CAG repeats are prone to breakage, and repair of the breaks can cause repeat contractions and expansions. In this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast chromosome. R-loops were further elevated upon deletion of yeast RNaseH genes and caused repeat fragility. A significant increase in CAG repeat contractions was also observed, consistent with previous human cell studies. Delet

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11

Gordenin, D. A., K. S. Lobachev, N. P. Degtyareva, A. L. Malkova, E. Perkins, and M. A. Resnick. "Inverted DNA repeats: a source of eukaryotic genomic instability." Molecular and Cellular Biology 13, no. 9 (1993): 5315–22. http://dx.doi.org/10.1128/mcb.13.9.5315-5322.1993.

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While inverted DNA repeats are generally acknowledged to be an important source of genetic instability in prokaryotes, relatively little is known about their effects in eukaryotes. Using bacterial transposon Tn5 and its derivatives, we demonstrate that long inverted repeats also cause genetic instability leading to deletion in the yeast Saccharomyces cerevisiae. Furthermore, they induce homologous recombination. Replication plays a major role in the deletion formation. Deletions are stimulated by a mutation in the DNA polymerase delta gene (pol3). The majority of deletions result from imprecis

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Gordenin, D. A., K. S. Lobachev, N. P. Degtyareva, A. L. Malkova, E. Perkins, and M. A. Resnick. "Inverted DNA repeats: a source of eukaryotic genomic instability." Molecular and Cellular Biology 13, no. 9 (1993): 5315–22. http://dx.doi.org/10.1128/mcb.13.9.5315.

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While inverted DNA repeats are generally acknowledged to be an important source of genetic instability in prokaryotes, relatively little is known about their effects in eukaryotes. Using bacterial transposon Tn5 and its derivatives, we demonstrate that long inverted repeats also cause genetic instability leading to deletion in the yeast Saccharomyces cerevisiae. Furthermore, they induce homologous recombination. Replication plays a major role in the deletion formation. Deletions are stimulated by a mutation in the DNA polymerase delta gene (pol3). The majority of deletions result from imprecis

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13

Ruiz Buendía, Gustavo A., Marion Leleu, Flavia Marzetta, et al. "Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion." Science Advances 6, no. 27 (2020): eaaz4012. http://dx.doi.org/10.1126/sciadv.aaz4012.

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Expanded CAG/CTG repeats underlie 13 neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington’s disease (HD). Upon expansion, disease loci acquire heterochromatic characteristics, which may provoke changes to chromatin conformation and thereby affect both gene expression and repeat instability. Here, we tested this hypothesis by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD–derived cells. We find that allele sizes ranging from 15 to 1700 repeats displayed similar chromatin interaction profiles. This was true for both loci and for alleles with differe

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14

Miret, J. J., L. Pessoa-Brandão, and R. S. Lahue. "Instability of CAG and CTG trinucleotide repeats in Saccharomyces cerevisiae." Molecular and Cellular Biology 17, no. 6 (1997): 3382–87. http://dx.doi.org/10.1128/mcb.17.6.3382.

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A quantitative genetic assay was developed to monitor alterations in tract lengths of trinucleotide repeat sequences in Saccharomyces cerevisiae. Insertion of (CAG)50 or (CTG)50 repeats into a promoter that drives expression of the reporter gene ADE8 results in loss of expression and white colony color. Contractions within the trinucleotide sequences to repeat lengths of 8 to 38 restore functional expression of the reporter, leading to red colony color. Reporter constructs including (CAG)50 or (CTG)50 repeat sequences were integrated into the yeast genome, and the rate of red colony formation

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15

Cho, In K., Faye Clever, Gordon Hong, and Anthony W. S. Chan. "CAG Repeat Instability in the Peripheral and Central Nervous System of Transgenic Huntington’s Disease Monkeys." Biomedicines 10, no. 8 (2022): 1863. http://dx.doi.org/10.3390/biomedicines10081863.

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Huntington’s Disease (HD) is an autosomal dominant disease that results in severe neurodegeneration with no cure. HD is caused by the expanded CAG trinucleotide repeat (TNR) on the Huntingtin gene (HTT). Although the somatic and germline expansion of the CAG repeats has been well-documented, the underlying mechanisms had not been fully delineated. Increased CAG repeat length is associated with a more severe phenotype, greater TNR instability, and earlier age of onset. The direct relationship between CAG repeat length and molecular pathogenesis makes TNR instability a useful measure of symptom

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16

Bhattacharyya, Saumitri, Michael L. Rolfsmeier, Michael J. Dixon, Kara Wagoner, and Robert S. Lahue. "Identification of RTG2 as a Modifier Gene for CTG·CAG Repeat Instability in Saccharomyces cerevisiae." Genetics 162, no. 2 (2002): 579–89. http://dx.doi.org/10.1093/genetics/162.2.579.

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Abstract Trinucleotide repeats (TNRs) undergo frequent mutations in families affected by TNR diseases and in model organisms. Much of the instability is conferred in cis by the sequence and length of the triplet tract. Trans-acting factors also modulate TNR instability risk, on the basis of such evidence as parent-of-origin effects. To help identify trans-acting modifiers, a screen was performed to find yeast mutants with altered CTG·CAG repeat mutation frequencies. The RTG2 gene was identified as one such modifier. In rtg2 mutants, expansions of CTG·CAG repeats show a modest increase in rate,

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17

Currey, Nicola, Joseph J. Daniel, Dessislava N. Mladenova, Jane E. Dahlstrom, and Maija R. J. Kohonen-Corish. "Microsatellite Instability in Mouse Models of Colorectal Cancer." Canadian Journal of Gastroenterology and Hepatology 2018 (2018): 1–7. http://dx.doi.org/10.1155/2018/6152928.

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Microsatellite instability (MSI) is caused by DNA mismatch repair deficiency and is an important prognostic and predictive biomarker in colorectal cancer but relatively few studies have exploited mouse models in the study of its clinical utility. Furthermore, most previous studies have looked at MSI in the small intestine rather than the colon of mismatch repair deficient Msh2-knockout (KO) mice. Here we compared Msh2-KO, p53-KO, and wild type (WT) mice that were treated with the carcinogen azoxymethane (AOM) and the nonsteroidal anti-inflammatory drug sulindac or received no treatment. The in

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18

Persi, Erez, Davide Prandi, Yuri I. Wolf, et al. "Proteomic and genomic signatures of repeat instability in cancer and adjacent normal tissues." Proceedings of the National Academy of Sciences 116, no. 34 (2019): 16987–96. http://dx.doi.org/10.1073/pnas.1908790116.

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Repetitive sequences are hotspots of evolution at multiple levels. However, due to difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content, beyond microsatellites, in proteomes and genomes directly from proteomic and genomic raw data. This method was applied to a wide range of tumors and normal tissues. We identify high similarity between repeat instability patterns in tumors and their patient-matched adjacent normal tissues. Nonetheless, tumor

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19

Chatterjee, Nimrat, Yunfu Lin, Beatriz A. Santillan, Patricia Yotnda, and John H. Wilson. "Environmental stress induces trinucleotide repeat mutagenesis in human cells." Proceedings of the National Academy of Sciences 112, no. 12 (2015): 3764–69. http://dx.doi.org/10.1073/pnas.1421917112.

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The dynamic mutability of microsatellite repeats is implicated in the modification of gene function and disease phenotype. Studies of the enhanced instability of long trinucleotide repeats (TNRs)—the cause of multiple human diseases—have revealed a remarkable complexity of mutagenic mechanisms. Here, we show that cold, heat, hypoxic, and oxidative stresses induce mutagenesis of a long CAG repeat tract in human cells. We show that stress-response factors mediate the stress-induced mutagenesis (SIM) of CAG repeats. We show further that SIM of CAG repeats does not involve mismatch repair, nucleot

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Higham, Catherine F., and Darren G. Monckton. "Modelling and inference reveal nonlinear length-dependent suppression of somatic instability for small disease associated alleles in myotonic dystrophy type 1 and Huntington disease." Journal of The Royal Society Interface 10, no. 88 (2013): 20130605. http://dx.doi.org/10.1098/rsif.2013.0605.

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More than 20 human genetic diseases are associated with inheriting an unstable expanded DNA simple sequence tandem repeat, for example, CTG (cytosine–thymine–guanine) repeats in myotonic dystrophy type 1 (DM1) and CAG (cytosine–adenine–guanine) repeats in Huntington disease (HD). These sequences mutate by changing the number of repeats not just between generations, but also during the lifetime of affected individuals. Levels of somatic instability contribute to disease onset and progression but as changes are tissue-specific, age- and repeat length-dependent, interpretation of the level of som

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Lai, Yanhao, Nicole Diaz, Rhyisa Armbrister, Irina Agoulnik, and Yuan Liu. "DNA Base Damage Repair Crosstalks with Chromatin Structures to Contract Expanded GAA Repeats in Friedreich’s Ataxia." Biomolecules 14, no. 7 (2024): 809. http://dx.doi.org/10.3390/biom14070809.

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Trinucleotide repeat (TNR) expansion is the cause of over 40 neurodegenerative diseases, including Huntington’s disease and Friedreich’s ataxia (FRDA). There are no effective treatments for these diseases due to the poor understanding of molecular mechanisms underlying somatic TNR expansion and contraction in neural systems. We and others have found that DNA base excision repair (BER) actively modulates TNR instability, shedding light on the development of effective treatments for the diseases by contracting expanded repeats through DNA repair. In this study, temozolomide (TMZ) was employed as

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22

Loupe, Jacob M., Ricardo Mouro Pinto, Kyung-Hee Kim, et al. "Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington’s disease knock-in mice is blocked by Mlh1 knock-out." Human Molecular Genetics 29, no. 18 (2020): 3044–53. http://dx.doi.org/10.1093/hmg/ddaa196.

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Abstract Recent genome-wide association studies of age-at-onset in Huntington’s disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-

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Maurer, D. J., B. L. O'Callaghan, and D. M. Livingston. "Orientation dependence of trinucleotide CAG repeat instability in Saccharomyces cerevisiae." Molecular and Cellular Biology 16, no. 12 (1996): 6617–22. http://dx.doi.org/10.1128/mcb.16.12.6617.

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To examine the chromosomal stability of repetitions of the trinucleotide CAG, we have cloned CAG repeat tracts onto the 3' end of the Saccharomyces cerevisiae ADE2 gene and placed the appended gene into the ARO2 locus of chromosome VII. Examination of chromosomal DNA from sibling colonies arising from clonal expansion of strains harboring repeat tracts showed that repeat tracts often change in length. Most changes in tract length are decreases, but rare increases also occur. Longer tracts are more unstable than smaller tracts. The most unstable tracts, of 80 to 90 repeats, undergo changes at r

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Hayward, Bruce E., and Karen Usdin. "Mechanisms of Genome Instability in the Fragile X-Related Disorders." Genes 12, no. 10 (2021): 1633. http://dx.doi.org/10.3390/genes12101633.

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The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are pron

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Grishchenko, I. V., A. A. Tulupov, Y. M. Rymareva, et al. "A transgenic cell line with inducible transcription for studying (CGG)n repeat expansion mechanisms." Vavilov Journal of Genetics and Breeding 25, no. 1 (2021): 117–24. http://dx.doi.org/10.18699/vj21.014.

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There are more than 30 inherited human disorders connected with repeat expansion (myotonic dystrophy type I, Huntington’s disease, Fragile X syndrome). Fragile X syndrome is the most common reason for inherited intellectual disability in the human population. The ways of the expansion development remain unclear. An important feature of expanded repeats is the ability to form stable alternative DNA secondary structures. There are hypotheses about the nature of repeat instability. It is proposed that these DNA secondary structures can block various stages of DNA metabolism processes, such as rep

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Liao, Xingyu, Kang Hu, Adil Salhi, You Zou, Jianxin Wang, and Xin Gao. "msRepDB: a comprehensive repetitive sequence database of over 80 000 species." Nucleic Acids Research 50, no. D1 (2021): D236—D245. http://dx.doi.org/10.1093/nar/gkab1089.

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Abstract Repeats are prevalent in the genomes of all bacteria, plants and animals, and they cover nearly half of the Human genome, which play indispensable roles in the evolution, inheritance, variation and genomic instability, and serve as substrates for chromosomal rearrangements that include disease-causing deletions, inversions, and translocations. Comprehensive identification, classification and annotation of repeats in genomes can provide accurate and targeted solutions towards understanding and diagnosis of complex diseases, optimization of plant properties and development of new drugs.

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Spiro, Craig, and Cynthia T. McMurray. "Nuclease-Deficient FEN-1 Blocks Rad51/BRCA1-Mediated Repair and Causes Trinucleotide Repeat Instability." Molecular and Cellular Biology 23, no. 17 (2003): 6063–74. http://dx.doi.org/10.1128/mcb.23.17.6063-6074.2003.

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ABSTRACT Previous studies have shown that expansion-prone repeats form structures that inhibit human flap endonuclease (FEN-1). We report here that faulty processing by FEN-1 initiates repeat instability in mammalian cells. Disease-length CAG tracts in Huntington's disease mice heterozygous for FEN-1 display a tendency toward expansions over contractions during intergenerational inheritance compared to those in homozygous wild-type mice. Further, with regard to human cells expressing a nuclease-defective FEN-1, we provide direct evidence that an unprocessed FEN-1 substrate is a precursor to in

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Radvanszky, Jan, Michaela Hyblova, Eva Radvanska, et al. "Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles." Journal of Clinical Medicine 10, no. 17 (2021): 3934. http://dx.doi.org/10.3390/jcm10173934.

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Myotonic dystrophy type 2 (DM2) is caused by expansion of a (CCTG)n repeat in the cellular retroviral nucleic acid-binding protein (CNBP) gene. The sequence of the repeat is most commonly interrupted and is stably inherited in the general population. Although expanded alleles, premutation range and, in rare cases, also non-disease associated alleles containing uninterrupted CCTG tracts have been described, the threshold between these categories is poorly characterised. Here, we describe four families with members reporting neuromuscular complaints, in whom we identified altogether nine ambiguo

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Sia, E. A., R. J. Kokoska, M. Dominska, P. Greenwell, and T. D. Petes. "Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes." Molecular and Cellular Biology 17, no. 5 (1997): 2851–58. http://dx.doi.org/10.1128/mcb.17.5.2851.

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We examined the stability of microsatellites of different repeat unit lengths in Saccharomyces cerevisiae strains deficient in DNA mismatch repair. The msh2 and msh3 mutations destabilized microsatellites with repeat units of 1, 2, 4, 5, and 8 bp; a poly(G) tract of 18 bp was destabilized several thousand-fold by the msh2 mutation and about 100-fold by msh3. The msh6 mutations destabilized microsatellites with repeat units of 1 and 2 bp but had no effect on microsatellites with larger repeats. These results argue that coding sequences containing repetitive DNA tracts will be preferred target s

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Smirnov, Evgeny, Nikola Chmúrčiaková, František Liška, Pavla Bažantová, and Dušan Cmarko. "Variability of Human rDNA." Cells 10, no. 2 (2021): 196. http://dx.doi.org/10.3390/cells10020196.

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In human cells, ribosomal DNA (rDNA) is arranged in ten clusters of multiple tandem repeats. Each repeat is usually described as consisting of two parts: the 13 kb long ribosomal part, containing three genes coding for 18S, 5.8S and 28S RNAs of the ribosomal particles, and the 30 kb long intergenic spacer (IGS). However, this standard scheme is, amazingly, often altered as a result of the peculiar instability of the locus, so that the sequence of each repeat and the number of the repeats in each cluster are highly variable. In the present review, we discuss the causes and types of human rDNA i

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Rolfsmeier, Michael L., Michael J. Dixon, Luis Pessoa-Brandão, Richard Pelletier, Juan José Miret, and Robert S. Lahue. "Cis-Elements Governing Trinucleotide Repeat Instability in Saccharomyces cerevisiae." Genetics 157, no. 4 (2001): 1569–79. http://dx.doi.org/10.1093/genetics/157.4.1569.

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Abstract Trinucleotide repeat (TNR) instability in humans is governed by unique cis-elements. One element is a threshold, or minimal repeat length, conferring frequent mutations. Since thresholds have not been directly demonstrated in model systems, their molecular nature remains uncertain. Another element is sequence specificity. Unstable TNR sequences are almost always CNG, whose hairpin-forming ability is thought to promote instability by inhibiting DNA repair. To understand these cis-elements further, TNR expansions and contractions were monitored by yeast genetic assays. A threshold of ∼1

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Khristich, Alexandra N., Jillian F. Armenia, Robert M. Matera, Anna A. Kolchinski, and Sergei M. Mirkin. "Large-scale contractions of Friedreich’s ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability." Proceedings of the National Academy of Sciences 117, no. 3 (2020): 1628–37. http://dx.doi.org/10.1073/pnas.1913416117.

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Friedreich’s ataxia (FRDA) is a human hereditary disease caused by the presence of expanded (GAA)n repeats in the first intron of the FXN gene [V. Campuzano et al., Science 271, 1423–1427 (1996)]. In somatic tissues of FRDA patients, (GAA)n repeat tracts are highly unstable, with contractions more common than expansions [R. Sharma et al., Hum. Mol. Genet. 11, 2175–2187 (2002)]. Here we describe an experimental system to characterize GAA repeat contractions in yeast and to conduct a genetic analysis of this process. We found that large-scale contraction is a one-step process, resulting in a med

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Mansour, Ahmed A., Carine Tornier, Elisabeth Lehmann, Michel Darmon, and Oliver Fleck. "Control of GT Repeat Stability in Schizosaccharomyces pombe by Mismatch Repair Factors." Genetics 158, no. 1 (2001): 77–85. http://dx.doi.org/10.1093/genetics/158.1.77.

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Abstract The mismatch repair (MMR) system ensures genome integrity by removing mispaired and unpaired bases that originate during replication. A major source of mutational changes is strand slippage in repetitive DNA sequences without concomitant repair. We established a genetic assay that allows measuring the stability of GT repeats in the ade6 gene of Schizosaccharomyces pombe. In repair-proficient strains most of the repeat variations were insertions, with addition of two nucleotides being the most frequent event. GT repeats were highly destabilized in strains defective in msh2 or pms1. In

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Tabolacci, Elisabetta, Veronica Nobile, Cecilia Pucci, and Pietro Chiurazzi. "Mechanisms of the FMR1 Repeat Instability: How Does the CGG Sequence Expand?" International Journal of Molecular Sciences 23, no. 10 (2022): 5425. http://dx.doi.org/10.3390/ijms23105425.

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A dynamic mutation in exon 1 of the FMR1 gene causes Fragile X-related Disorders (FXDs), due to the expansion of an unstable CGG repeat sequence. Based on the CGG sequence size, two types of FMR1 alleles are possible: “premutation” (PM, with 56-200 CGGs) and “full mutation” (FM, with >200 triplets). Premutated females are at risk of transmitting a FM allele that, when methylated, epigenetically silences FMR1 and causes Fragile X syndrome (FXS), a very common form of inherited intellectual disability (ID). Expansions events of the CGG sequence are predominant over contractions and are respon

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Guo, Pei, and Sik Lok Lam. "Unusual structures of CCTG repeats and their participation in repeat expansion." Biomolecular Concepts 7, no. 5-6 (2016): 331–40. http://dx.doi.org/10.1515/bmc-2016-0024.

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AbstractCCTG repeat expansion in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene has been identified to be the genetic cause of myotonic dystrophy type 2 (DM2). Yet the underlying reasons for the genetic instability in CCTG repeats remain elusive. In recent years, CCTG repeats have been found to form various types of unusual secondary structures including mini-dumbbell (MDB), hairpin and dumbbell, revealing that there is a high structural diversity in CCTG repeats intrinsically. Upon strand slippage, the formation of unusual structures in the nascent strand during DNA replica

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Cummings, Damian M., Yasaman Alaghband, Miriam A. Hickey, et al. "A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease." Journal of Neurophysiology 107, no. 2 (2012): 677–91. http://dx.doi.org/10.1152/jn.00762.2011.

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The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ∼150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse rela

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Bichara, Marc, Isabelle Pinet, Sylvie Schumacher, and Robert P. P. Fuchs. "Mechanisms of Dinucleotide Repeat Instability in Escherichia coli." Genetics 154, no. 2 (2000): 533–42. http://dx.doi.org/10.1093/genetics/154.2.533.

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Abstract The high level of polymorphism of microsatellites has been used for a variety of purposes such as positional cloning of genes associated with diseases, forensic medicine, and phylogenetic studies. The discovery that microsatellites are associated with human diseases, not only as markers of risk but also directly in disease pathogenesis, has triggered a renewed interest in understanding the mechanism of their instability. In this work we have investigated the role of DNA replication, long patch mismatch repair, and transcription on the genetic instability of all possible combinations o

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Savouret, Cédric, Corinne Garcia-Cordier, Jérôme Megret, Hein te Riele, Claudine Junien, and Geneviève Gourdon. "MSH2-Dependent Germinal CTG Repeat Expansions Are Produced Continuously in Spermatogonia from DM1 Transgenic Mice." Molecular and Cellular Biology 24, no. 2 (2004): 629–37. http://dx.doi.org/10.1128/mcb.24.2.629-637.2004.

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ABSTRACT Myotonic dystrophy type 1 is a neuromuscular affection associated with the expansion of an unstable CTG repeat in the DM protein kinase gene. The disease is characterized by somatic tissue-specific mosaicism and very high intergenerational instability with a strong bias towards expansions. We used transgenic mice carrying more than 300 unstable CTG repeats within their large human genomic environment to investigate the dynamics of CTG repeat germinal mosaicism in males. Germinal mosaicism towards expansions was already present in spermatozoa at 7 weeks of age and continued to increase

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López, Castel Arturo. "Absence of MutSβ leads to the formation of slipped-DNA for CTG/CAG contractions at primate replication forks". DNA Repair 42 (1 червня 2016): 107–18. https://doi.org/10.1016/j.dnarep.2016.04.002.

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Typically disease-causing CAG/CTG repeats expand, but rare affected families can display high levels of contraction of the expanded repeat amongst offspring. Understanding instability is important since arresting expansions or enhancing contractions could be clinically beneficial. The MutSβ mismatch repair complex is required for CAG/CTG expansions in mice and patients. Oddly, by unknown mechanisms MutSβ-deficient mice incur contractions instead of expansions. Replication using CTG or CAG as the lagging strand template is known to cause contractions or expansions respectively; howeve

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Dunn and Anderson. "To Repeat or Not to Repeat: Repetitive Sequences Regulate Genome Stability in Candida albicans." Genes 10, no. 11 (2019): 866. http://dx.doi.org/10.3390/genes10110866.

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Genome instability often leads to cell death but can also give rise to innovative genotypic and phenotypic variation through mutation and structural rearrangements. Repetitive sequences and chromatin architecture in particular are critical modulators of recombination and mutability. In Candida albicans, four major classes of repeats exist in the genome: telomeres, subtelomeres, the major repeat sequence (MRS), and the ribosomal DNA (rDNA) locus. Characterization of these loci has revealed how their structure contributes to recombination and either promotes or restricts sequence evolution. The

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Auer, Rebecca L., Christopher Jones, Roman A. Mullenbach, et al. "Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia." Blood 97, no. 2 (2001): 509–15. http://dx.doi.org/10.1182/blood.v97.2.509.

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Abstract Chromosome 11q deletions are frequently observed in chronic lymphocytic leukemia (CLL) in association with progressive disease and a poor prognosis. A minimal region of deletion has been assigned to 11q22-q23. Trinucleotide repeats have been associated with anticipation in disease, and evidence of anticipation has been observed in various malignancies including CLL. Loss of heterozygosity at 11q22-23 is common in a wide range of cancers, suggesting this is an unstable area prone to chromosome breakage. The location of 8 CCG-trinucleotide repeats on 11q was determined by Southern blot

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Brown, Rebecca E., Xiaofeng A. Su, Stacey Fair, et al. "The RNA export and RNA decay complexes THO and TRAMP prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions." PLOS Biology 20, no. 12 (2022): e3001940. http://dx.doi.org/10.1371/journal.pbio.3001940.

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Expansion of structure-forming CAG/CTG repetitive sequences is the cause of several neurodegenerative disorders and deletion of repeats is a potential therapeutic strategy. Transcription-associated mechanisms are known to cause CAG repeat instability. In this study, we discovered that Thp2, an RNA export factor and member of the THO (suppressors of transcriptional defects of hpr1Δ by overexpression) complex, and Trf4, a key component of the TRAMP (Trf4/5-Air1/2-Mtr4 polyadenylation) complex involved in nuclear RNA polyadenylation and degradation, are necessary to prevent CAG fragility and repe

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Henderson, S. T., and T. D. Petes. "Instability of simple sequence DNA in Saccharomyces cerevisiae." Molecular and Cellular Biology 12, no. 6 (1992): 2749–57. http://dx.doi.org/10.1128/mcb.12.6.2749-2757.1992.

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All eukaryotic genomes thus far examined contain simple sequence repeats. A particularly common simple sequence in many organisms (including humans) consists of tracts of alternating GT residues on one strand. Allelic poly(GT) tracts are often of different lengths in different individuals, indicating that they are likely to be unstable. We examined the instability of poly(GT) and poly(G) tracts in the yeast Saccharomyces cerevisiae. We found that these tracts were dramatically unstable, altering length at a minimal rate of 10(-4) events per division. Most of the changes involved one or two rep

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Henderson, S. T., and T. D. Petes. "Instability of simple sequence DNA in Saccharomyces cerevisiae." Molecular and Cellular Biology 12, no. 6 (1992): 2749–57. http://dx.doi.org/10.1128/mcb.12.6.2749.

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All eukaryotic genomes thus far examined contain simple sequence repeats. A particularly common simple sequence in many organisms (including humans) consists of tracts of alternating GT residues on one strand. Allelic poly(GT) tracts are often of different lengths in different individuals, indicating that they are likely to be unstable. We examined the instability of poly(GT) and poly(G) tracts in the yeast Saccharomyces cerevisiae. We found that these tracts were dramatically unstable, altering length at a minimal rate of 10(-4) events per division. Most of the changes involved one or two rep

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Ruskin, B., and G. R. Fink. "Mutations in POL1 increase the mitotic instability of tandem inverted repeats in Saccharomyces cerevisiae." Genetics 134, no. 1 (1993): 43–56. http://dx.doi.org/10.1093/genetics/134.1.43.

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Abstract Tandem inverted repeats (TIRs or hairpins) of 30 and 80 base-pair unit lengths are unstable mitotically in yeast (Saccharomyces cerevisiae). TIR instability results from deletions that remove part or all of the presumed hairpin structure from the chromosome. At least one deletion endpoint is always at or near the base of the hairpin, and almost all of the repaired junctions occur within short direct sequence repeats of 4 to 9 base pairs. The frequency of this event, which we call "hairpin excision," is influenced by chromosomal position, length of the inverted repeats, and the distanc

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Kilburn, April E., Martin J. Shea, R. Geoffrey Sargent, and John H. Wilson. "Insertion of a Telomere Repeat Sequence into a Mammalian Gene Causes Chromosome Instability." Molecular and Cellular Biology 21, no. 1 (2001): 126–35. http://dx.doi.org/10.1128/mcb.21.1.126-135.2001.

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ABSTRACT Telomere repeat sequences cap the ends of eucaryotic chromosomes and help stabilize them. At interstitial sites, however, they may destabilize chromosomes, as suggested by cytogenetic studies in mammalian cells that correlate interstitial telomere sequence with sites of spontaneous and radiation-induced chromosome rearrangements. In no instance is the length, purity, or orientation of the telomere repeats at these potentially destabilizing interstitial sites known. To determine the effects of a defined interstitial telomere sequence on chromosome instability, as well as other aspects

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Schnabel, E. L., and A. L. Jones. "Instability of a pEA29 Marker in Erwinia amylovora Previously Used for Strain Classification." Plant Disease 82, no. 12 (1998): 1334–36. http://dx.doi.org/10.1094/pdis.1998.82.12.1334.

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We examined the use of previously observed restriction fragment length polymorphisms (RFLPs) of a polymerase chain reaction (PCR)-amplified fragment of plasmid pEA29 for differentiating strains of Erwinia amylovora. The PCR fragment from E. amylovora strain CA11 contains a region of 8-bp tandem repeats which is predicted to cause the RFLPs. Examination of a collection of 93 strains revealed the repeat sequence GATTACA(GAATTACA)nGAATTACA in pEA29 with n ranging from 3 to 14. Selected strains were examined after growth in liquid culture to establish the stability of this character. Four strains

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Feng, Liqing, Ying Zhuang, Dagang Tian, Linwei Zhou, Jinbin Wang, and Jingping Fang. "Integrative Genomic and Cytogenetic Analyses Reveal the Landscape of Typical Tandem Repeats in Water Hyacinth." Horticulturae 11, no. 6 (2025): 657. https://doi.org/10.3390/horticulturae11060657.

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Tandem repeats in eukaryotic genomes exhibit intrinsic instability that drives rapid evolutionary diversification. However, their evolutionary dynamics in allopolyploid species such as the water hyacinth (Pontederia crassipes or Eichhornia crassipes) remain largely unexplored. Our study used integrated genomic and cytogenetic analyses of this allotetraploid species to characterize five representative tandem repeats, revealing distinct genomic distribution patterns and copy number polymorphisms. The highly abundant centromeric tandem repeat, putative CentEc, was co-localized with the centromeri

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Slavicek, James M., and Hallie M. Krider. "The organization and composition of the ribosomal RNA gene non-transcribed spacer of D. busckii is unique among the drosophilids." Genetical Research 50, no. 3 (1987): 173–80. http://dx.doi.org/10.1017/s0016672300023661.

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SummarySeveral ribosomal RNA (rRNA) genes from D. busckii were cloned and characterized. The prominent repeat classes have lengths of 12·8 and 13·6 kb and lack 28S introns. rRNA genes were cloned containing 28S insertions which exhibit heterogeneity in size and sequence. The non-transcribed spacer (NTS) contains two regions composed of different repeated sequences that exhibit pronounced instability in HB 101. NTS region II, centrally located within the NTS, contains predominately 11 or 16 HincII generated 160 bp repeats. NTS region III, next to the 18S gene, contains repeats that are variable

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Gray, Steven J., Jeannine Gerhardt, Walter Doerfler, Lawrence E. Small, and Ellen Fanning. "An Origin of DNA Replication in the Promoter Region of the Human Fragile X Mental Retardation (FMR1) Gene." Molecular and Cellular Biology 27, no. 2 (2006): 426–37. http://dx.doi.org/10.1128/mcb.01382-06.

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ABSTRACT Fragile X syndrome, the most common form of inherited mental retardation in males, arises when the normally stable 5 to 50 CGG repeats in the 5′ untranslated region of the fragile X mental retardation protein 1 (FMR1) gene expand to over 200, leading to DNA methylation and silencing of the FMR1 promoter. Although the events that trigger local CGG expansion remain unknown, the stability of trinucleotide repeat tracts is affected by their position relative to an origin of DNA replication in model systems. Origins of DNA replication in the FMR1 locus have not yet been described. Here, we

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