Uninterrupted CCTG tracts in the myotonic dystrophy type 2 associated locus

Radvánszky, Ján; Surovy, Milan; Polák, Emil; Kádaši, Ľudevít

doi:10.1016/j.nmd.2013.02.013

Cited by 19 publications

(39 citation statements)

References 29 publications

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“…In other words, a loss of AGG interruption likely predisposes CGG repeat tracts to large-scale expansions (149,152). Generally, the stabilizing role of interruptions is common for expandable repeats and has been reported for GAA (153,154), CAG (38,128,129,(155)(156)(157)(158)(159)(160)(161)(162), CCTG (54,58,(163)(164)(165), and other repeats in somatic tissues, intergenerational transmission, and experimental systems.…”

Section: Relationship Between Repeat Size and Instabilitymentioning

confidence: 99%

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

Khristich

Mirkin

2020

Journal of Biological Chemistry

216

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: Relationship Between Repeat Size and Instabilitymentioning

confidence: 99%

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

Khristich

Mirkin

2020

Journal of Biological Chemistry

216

239

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“…Notably, no mutations causing DM have been reported within the DMPK coding region, arguing against a direct role of the protein in the pathogenesis of DM; nor have coding mutations in the FMR1 gene been linked to FXTAS, though such mutations do lead to fragile X syndrome [31,38,64,119]. Furthermore, an intronic CCTG-repeat expansion in an unrelated gene, ZNF9 , leads to a highly similar form of myotonic dystrophy (DM2) [112,130]. …”

Section: Initial Events In the Pathogenesis Of Fxtas And Other Premutmentioning

confidence: 99%

Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms

2013

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Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers.

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“…Therefore we expect that the unusual mini-dumbbell formed in interrupted CCTG repeats can be caught and fixed easily by mismatch repair (MMR). However, if the mini-dumbbell is formed in uninterrupted large-sized alleles (containing 55 to more than 11 000 CCTG repeats) which are considered to be possible DM2 premutations [33], we expect that the mini-dumbbell can shift continuously in the 5 0 or 3 0 direction with its adjacent CCTG repeats, providing an efficient escape pathway from MMR. In contrast to DM1 CTG repeats, correct repair, escaped repair and errorprone repair were all observed in in vitro analysis of the fidelity by which slipped intermediates were processed by human cell proteins [34].…”

Section: Biological Implications Of the Mini-dumbbell In Cctg Repeatsmentioning

confidence: 99%

New insights into the genetic instability in CCTG repeats

Guo

Lam

2015

FEBS Letters

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a b s t r a c tTetranucleotide CCTG repeat expansion is associated with myotonic dystrophy type 2, which is an inherited and progressive muscle degeneration disease. Yet, no cure is available and the molecular mechanism of repeat expansion remains elusive. In this study, we used high-resolution nuclear magnetic resonance spectroscopy to reveal a mini-dumbbell structure formed by two CCTG repeats. Upon slippage in the nascent strand during DNA replication, the formation of the mini-dumbbell provides a possible pathway for a two-repeat expansion. In addition, fast exchange between two competing mini-dumbbells among three repeats results in a mini-loop structure that accounts for one-repeat expansion. These mini-dumbbell and mini-loop intermediates can also co-exist at multiple sites in CCTG repeats, leading to three or larger size repeat expansions.

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Uninterrupted CCTG tracts in the myotonic dystrophy type 2 associated locus

Cited by 19 publications

References 29 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

Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms

New insights into the genetic instability in CCTG repeats

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