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NeuroRx : the Journal of the American... Apr 2004Huntington's disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children... (Review)
Review
Huntington's disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children of HD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. HD is a "trinucleotide repeat" disorder, which is caused by an increase in the number of CAG repeats in the HD gene. Repeats of 40 or larger are associated with disease expression, whereas repeats of 26 and smaller are normal. Intermediate numbers of repeats, between 27 and 35, are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendents. Repeats of 36-39 are associated with reduced penetrance whereby some develop HD and others do not. The identification of the genetic defect in HD permits direct genetic testing for the presence of the gene alteration responsible for the disease. Tests may be performed in three circumstances: (1) confirmation of diagnosis, (2) predictive testing of persons at genetic risk for inheriting HD, and (3) prenatal testing. Testing is widely available and much experience has been gained with protocols that assist the individual in making an informed choice about test options, and minimize the occurrence of adverse emotional outcomes.
Topics: Humans; Huntingtin Protein; Huntington Disease; Nerve Tissue Proteins; Nuclear Proteins; Trinucleotide Repeats
PubMed: 15717026
DOI: 10.1602/neurorx.1.2.255 -
Cells Apr 2021Trinucleotide repeats are a peculiar class of microsatellites whose expansions are responsible for approximately 30 human neurological or developmental disorders. The... (Review)
Review
Trinucleotide repeats are a peculiar class of microsatellites whose expansions are responsible for approximately 30 human neurological or developmental disorders. The molecular mechanisms responsible for these expansions in humans are not totally understood, but experiments in model systems such as yeast, transgenic mice, and human cells have brought evidence that the mismatch repair machinery is involved in generating these expansions. The present review summarizes, in the first part, the role of mismatch repair in detecting and fixing the DNA strand slippage occurring during microsatellite replication. In the second part, key molecular differences between normal microsatellites and those that show a bias toward expansions are extensively presented. The effect of mismatch repair mutants on microsatellite expansions is detailed in model systems, and in vitro experiments on mismatched DNA substrates are described. Finally, a model presenting the possible roles of the mismatch repair machinery in microsatellite expansions is proposed.
Topics: Animals; DNA; DNA Mismatch Repair; DNA Repair; Genotype; Humans; Meiosis; Mice; Mice, Transgenic; Microsatellite Repeats; Mitosis; MutL Proteins; MutS Proteins; Recombination, Genetic; Saccharomyces cerevisiae; Schizosaccharomyces; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 33925919
DOI: 10.3390/cells10051019 -
PLoS Genetics Oct 2021Disease-associated trinucleotide repeats form secondary DNA structures that interfere with replication and repair. Replication has been implicated as a mechanism that...
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 specifically addressed the fidelity of a restarted fork as it replicates through a CAG/CTG repeat tract and its effect on repeat instability. To do this, we used a well-characterized site-specific replication fork barrier (RFB) system in fission yeast that creates an inducible and highly efficient stall that is known to restart by recombination-dependent replication (RDR), in combination with long CAG repeat tracts inserted at various distances and orientations with respect to the RFB. We find that replication by the restarted fork exhibits low fidelity through repeat sequences placed 2-7 kb from the RFB, exhibiting elevated levels of Rad52- and Rad8ScRad5/HsHLTF-dependent instability. CAG expansions and contractions are not elevated to the same degree when the tract is just in front or behind the barrier, suggesting that the long-traveling Polδ-Polδ restarted fork, rather than fork reversal or initial D-loop synthesis through the repeat during stalling and restart, is the greatest source of repeat instability. The switch in replication direction that occurs due to replication from a converging fork while the stalled fork is held at the barrier is also a significant contributor to the repeat instability profile. Our results shed light on a long-standing question of how fork stalling and RDR contribute to expansions and contractions of structure-forming trinucleotide repeats, and reveal that tolerance to replication stress by fork restart comes at the cost of increased instability of repetitive sequences.
Topics: DNA; DNA Repair; DNA Replication; Genomic Instability; Schizosaccharomyces; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 34673780
DOI: 10.1371/journal.pgen.1009863 -
BioFactors (Oxford, England) 2013Unstable repeat diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human... (Review)
Review
Unstable repeat diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human neurological diseases are caused by instability, predominantly, expansion of microsatellite sequences. Changes in the repeat size initiate a cascade of pathological processes, frequently characteristic of a unique disease or a small subgroup of the URDs. Understanding of both the mechanism of repeat instability and molecular consequences of the repeat expansions is critical to developing successful therapies for these diseases. Recent technological breakthroughs in whole genome, transcriptome and proteome analyses will almost certainly lead to new discoveries regarding the mechanisms of repeat instability, the pathogenesis of URDs, and will facilitate development of novel therapeutic approaches. The aim of this review is to give a general overview of unstable repeats diseases, highlight the complexities of these diseases, and feature the emerging discoveries in the field.
Topics: Animals; Disease; Genetic Variation; Genomic Instability; Humans; Minisatellite Repeats; Tandem Repeat Sequences; Trinucleotide Repeats
PubMed: 23233240
DOI: 10.1002/biof.1060 -
International Journal of Molecular... May 2022Among types of trinucleotide repeats, there is some disproportion in the frequency of their occurrence in the human exome. This research presents new data describing the...
Among types of trinucleotide repeats, there is some disproportion in the frequency of their occurrence in the human exome. This research presents new data describing the folding and thermodynamic stability of short, tandem RNA repeats of 23 types, focusing on the rare, yet poorly analyzed ones. UV-melting experiments included the presence of PEG or potassium and magnesium ions to determine their effect on the stability of RNA repeats structures. Rare repeats predominantly stayed single-stranded but had the potential for base pairing with other partially complementary repeat tracts. A coexistence of suitably complementary repeat types in a single RNA creates opportunities for interaction in the context of the secondary structure of RNA. We searched the human transcriptome for model RNAs in which different, particularly rare trinucleotide repeats coexist and selected the and RNAs to study intramolecular interactions between the repeat tracts that they contain. In vitro secondary structure probing results showed that the UAA and UUG repeat tracts, present in 3' UTR, form a double helix, which separates one of its structural domains. For the RNA ORF fragment containing four short AGG repeat tracts and the CGU tract, we proved the formation of quadruplexes that blocked reverse transcription.
Topics: Base Pairing; Humans; RNA; Thermodynamics; Trinucleotide Repeats
PubMed: 35628656
DOI: 10.3390/ijms23105850 -
Nucleic Acids Research Jan 2012This review presents detailed information about the structure of triplet repeat RNA and addresses the simple sequence repeats of normal and expanded lengths in the... (Review)
Review
This review presents detailed information about the structure of triplet repeat RNA and addresses the simple sequence repeats of normal and expanded lengths in the context of the physiological and pathogenic roles played in human cells. First, we discuss the occurrence and frequency of various trinucleotide repeats in transcripts and classify them according to the propensity to form RNA structures of different architectures and stabilities. We show that repeats capable of forming hairpin structures are overrepresented in exons, which implies that they may have important functions. We further describe long triplet repeat RNA as a pathogenic agent by presenting human neurological diseases caused by triplet repeat expansions in which mutant RNA gains a toxic function. Prominent examples of these diseases include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome, which are triggered by mutant CUG and CGG repeats, respectively. In addition, we discuss RNA-mediated pathogenesis in polyglutamine disorders such as Huntington's disease and spinocerebellar ataxia type 3, in which expanded CAG repeats may act as an auxiliary toxic agent. Finally, triplet repeat RNA is presented as a therapeutic target. We describe various concepts and approaches aimed at the selective inhibition of mutant transcript activity in experimental therapies developed for repeat-associated diseases.
Topics: Humans; Nervous System Diseases; Proteins; RNA, Messenger; Repetitive Sequences, Nucleic Acid; Trinucleotide Repeat Expansion
PubMed: 21908410
DOI: 10.1093/nar/gkr729 -
Trends in Neurosciences Jun 2010A large number of human diseases are caused by expansion of repeat sequences - typically trinucleotide repeats - within the respective disease genes. The abnormally... (Review)
Review
A large number of human diseases are caused by expansion of repeat sequences - typically trinucleotide repeats - within the respective disease genes. The abnormally expanded sequence can lead to a variety of effects on the gene: sometimes the gene is silenced, but in many cases the expanded repeat sequences confer toxicity to the mRNA and, in the case of polyglutamine diseases, to the encoded protein. This article highlights mechanisms by which the mRNAs with abnormally expanded repeats can confer toxicity leading to neuronal dysfunction and loss. Greater understanding of these mechanisms will provide the foundation for therapeutic advances for this set of human disorders.
Topics: Animals; Humans; Nerve Degeneration; Nervous System Diseases; RNA; Trinucleotide Repeat Expansion
PubMed: 20398949
DOI: 10.1016/j.tins.2010.03.004 -
Nucleic Acids Research Jul 2014CNG repeats (where N denotes one of the four natural nucleotides) are abundant in the human genome. Their tendency to undergo expansion can lead to hereditary diseases... (Review)
Review
CNG repeats (where N denotes one of the four natural nucleotides) are abundant in the human genome. Their tendency to undergo expansion can lead to hereditary diseases known as TREDs (trinucleotide repeat expansion disorders). The toxic factor can be protein, if the abnormal gene is expressed, or the gene transcript, or both. The gene transcripts have attracted much attention in the biomedical community, but their molecular structures have only recently been investigated. Model RNA molecules comprising CNG repeats fold into long hairpins whose stems generally conform to an A-type helix, in which the non-canonical N-N pairs are flanked by C-G and G-C pairs. Each homobasic pair is accommodated in the helical context in a unique manner, with consequences for the local helical parameters, solvent structure, electrostatic potential and potential to interact with ligands. The detailed three-dimensional profiles of RNA CNG repeats can be used in screening of compound libraries for potential therapeutics and in structure-based drug design. Here is a brief survey of the CNG structures published to date.
Topics: Crystallography, X-Ray; Humans; Nuclear Magnetic Resonance, Biomolecular; Nucleic Acid Conformation; RNA; Thermodynamics; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 24939898
DOI: 10.1093/nar/gku536 -
Proceedings of the National Academy of... Aug 2023Human genome-wide association studies have identified and several DNA mismatch repair (MMR) genes as modifiers of Huntington's disease age of onset. In animal models,...
Human genome-wide association studies have identified and several DNA mismatch repair (MMR) genes as modifiers of Huntington's disease age of onset. In animal models, FAN1 prevents somatic expansion of CAG triplet repeats, whereas MMR proteins promote this process. To understand the molecular basis of these opposing effects, we evaluated FAN1 nuclease function on DNA extrahelical extrusions that represent key intermediates in triplet repeat expansion. Here, we describe a strand-directed, extrusion-provoked nuclease function of FAN1 that is activated by RFC, PCNA, and ATP at physiological ionic strength. Activation of FAN1 in this manner results in DNA cleavage in the vicinity of triplet repeat extrahelical extrusions thereby leading to their removal in human cell extracts. The role of PCNA and RFC is to confer strand directionality to the FAN1 nuclease, and this reaction requires a physical interaction between PCNA and FAN1. Using cell extracts, we show that FAN1-dependent CAG extrusion removal relies on a very short patch excision-repair mechanism that competes with MutSβ-dependent MMR which is characterized by longer excision tracts. These results provide a mechanistic basis for the role of FAN1 in preventing repeat expansion and could explain the antagonistic effects of MMR and FAN1 in disease onset/progression.
Topics: Humans; Cell Extracts; Endodeoxyribonucleases; Endonucleases; Exodeoxyribonucleases; Genome-Wide Association Study; Multifunctional Enzymes; Proliferating Cell Nuclear Antigen; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 37549289
DOI: 10.1073/pnas.2302103120 -
Trends in Genetics : TIG Jul 2009Trinucleotide repeat expansion underlies at least 17 neurological diseases. In affected individuals, the expanded locus is characterized by dramatic changes in chromatin... (Review)
Review
Trinucleotide repeat expansion underlies at least 17 neurological diseases. In affected individuals, the expanded locus is characterized by dramatic changes in chromatin structure and in repeat tract length. Interestingly, recent studies show that several chromatin modifiers, including a histone acetyltransferase, a DNA methyltransferase and the chromatin insulator CTCF can modulate repeat instability. Here, we propose that the unusual chromatin structure of expanded repeats directly impacts their instability. We discuss several potential models for how this might occur, including a role for DNA repair-dependent epigenetic reprogramming in increasing repeat instability, and the capacity of epigenetic marks to alter sense and antisense transcription, thereby affecting repeat instability.
Topics: Animals; Chromatin; Chromosome Aberrations; DNA Methylation; DNA Repair; Embryonic Development; Epigenesis, Genetic; Humans; Nervous System Diseases; Trinucleotide Repeat Expansion
PubMed: 19540013
DOI: 10.1016/j.tig.2009.04.007