Measuring Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo in Saccharomyces cerevisiae

Williams, Gregory M.; Surtees, Jennifer A.

doi:10.1007/978-1-4939-7306-4_30

Cited by 8 publications

(6 citation statements)

References 41 publications

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“…Interestingly, the effect of knocking out Msh6 or Exo1 has either a much smaller (420,423) or an opposite effect (422, 430) on repeat instability in mice. In agreement with mouse data, knocking out components of mismatch repair in other systems decreases CAG repeat instability rates (335,389,431,432), although some studies have failed to detect an effect (161,280,433). Instability of other repeats, such as GAA, also seems to be promoted by components of MMR, but to a lesser extent, and not specifically by MutS␤ (434 -439).…”

Section: Mmrsupporting

confidence: 76%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

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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 molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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Section: Mmrsupporting

confidence: 76%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

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“…It was shown that CAG and CTG trinucleotide repeats form imperfect hairpins in vitro (Gacy et al, 1995;Yu et al, 1995aYu et al, , 1995b. In addition, there is biochemical and genetical evidence that CAG and CTG hairpins interfere with the mismatch repair machinery, an important player of the expansion process, although its precise role is not totally clear (Foiry et al, 2006;Manley et al, 1999;Owen et al, 2005;Pearson et al, 1997;Pinto et al, 2013;Savouret et al, 2004;Slean et al, 2016;Tian et al, 2009;Tomé et al, 2009Tomé et al, , 2013Viterbo et al, 2016;Williams and Surtees, 2015). Most trinucleotide repeat transmissions from parents to children lead to repeat tract expansion.…”

Section: Introductionmentioning

confidence: 99%

TALEN-Induced Double-Strand Break Repair of CTG Trinucleotide Repeats

et al. 2018

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Trinucleotide repeat expansions involving CTG/CAG triplets are responsible for several neurodegenerative disorders, including myotonic dystrophy and Huntington's disease. Because expansions trigger the disease, contracting repeat length could be a possible approach to gene therapy for these disorders. Here, we show that a TALEN-induced double-strand break was very efficient at contracting expanded CTG repeats in yeast. We show that RAD51, POL32, and DNL4 are dispensable for double-strand break repair within CTG repeats, the only required genes being RAD50, SAE2, and RAD52. Resection was totally abolished in the absence of RAD50 on both sides of the break, whereas it was reduced in a sae2Δ mutant on the side of the break containing the longest repeat tract, suggesting that secondary structures at double-strand break ends must be removed by the Mre11-Rad50 complex and Sae2. Following the TALEN double-strand break, single-strand annealing occurred between both sides of the repeat tract, leading to repeat contraction.

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“…Large cloned arrays of human tandem DNA repeats inserted into the yeast genome 8 – 10 or carried by a plasmid 11 are stable across a wide array of size in a wild type background, allowing for identification of genetic pathways associated to repeat instability. Analyses of yeast mutant strains carrying tandem DNA repeats have allowed a better understanding of the roles of replication, DNA repair, recombination, transcription or DNA structures in genetic stability of trinucleotide repeats 12 or human G-rich minisatellites 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Locus specific engineering of tandem DNA repeats in the genome of Saccharomyces cerevisiae using CRISPR/Cas9 and overlapping oligonucleotides

Lancrey

Joubert

Boulé

2018

Sci Rep

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DNA repeats constitute a large part of genomes of multicellular eucaryotes. For a longtime considered as junk DNA, their role in genome organization and tuning of gene expression is being increasingly documented. Synthetic biology has so far largely ignored DNA repeats as regulatory elements to manipulate functions in engineered genomes. The yeast Saccharomyces cerevisiae has been a workhorse of synthetic biology, owing to its genetic tractability. Here we demonstrate the ability to synthetize, in a simple manner, tandem DNA repeats of various size by Cas9-assisted oligonucleotide in vivo assembly in this organism. We show that long tandem DNA repeats of several kilobases can be assembled in one step for different monomer size and G/C content. The combinatorial nature of the approach allows exploring a wide variety of design for building synthetic tandem repeated DNA directly at a given locus in the Saccharomyces cerevisiae genome. This approach provides a simple way to incorporate tandem DNA repeat in synthetic genome designs to implement regulatory functions.

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Measuring Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo in Saccharomyces cerevisiae

Cited by 8 publications

References 41 publications

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

TALEN-Induced Double-Strand Break Repair of CTG Trinucleotide Repeats

Locus specific engineering of tandem DNA repeats in the genome of Saccharomyces cerevisiae using CRISPR/Cas9 and overlapping oligonucleotides

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