DNA Mismatch Repair and its Role in Huntington’s Disease

Iyer, Ravi; Pluciennik, Anna

doi:10.3233/jhd-200438

Cited by 65 publications

(65 citation statements)

References 225 publications

(349 reference statements)

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“…The MMR pathway is best characterized for its role in correcting DNA mismatches generated during DNA replication but has additional functions in DNA recombination and in DNA damage signaling (reviewed in [47,151,152]). In mammals, MSH2-MSH6 dimers (MutS␣) primarily recognize base-base mismatches, whereas MSH2-MSH3 dimers (MutS␤) primarily recognize insertion-deletion loops.…”

Section: Mismatch Repair Factorsmentioning

confidence: 99%

“…For the purpose of this review, we use the term "DNA repair" to describe the process or function to which genes or pathways are traditionally assigned, rather than the functional outcome of that process in the context of expanded repeats. More specifically, and as an example, we use the term "mismatch repair" (MMR) to mean the canonical post-replicative pathway and its components [47], acknowledging that the specific functions of the proteins in the pathway may be different in the context of expanded repeats.…”

Section: Introductionmentioning

confidence: 99%

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Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Wheeler

Dion

2021

JHD

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At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction.

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Section: Mismatch Repair Factorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Wheeler

Dion

2021

JHD

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“…Swami et al [14] investigated somatic expansion in post-mortem DNA samples from HD patients, and showed that patients with particularly early-onset have a higher proportion of large expansions in the cortex. Most recently, genetic association studies in HD patient cohorts have revealed the association between DNA repair gene variants and age at motor signs of HD and HD progression [15][16][17][18][19]. These data suggest that somatic CAG repeat expansions contribute toward HD pathology.…”

Section: Introductionmentioning

confidence: 97%

Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation

Ciosi

Cumming

Chatzi

et al. 2021

JHD

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Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large (>50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions.

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“…Another clear prediction of the DNA replication slippage model is that loss of function mutations in the postreplicative DNA mismatch repair pathway should increase the frequency of expansions. This prediction was turned on its head in 1999, when Manley et al demonstrated that the complete reverse was true and that the obligate mammalian MutS homologue Msh2 was absolutely required to generate somatic expansions [232] (see Iyer and Pluciennik, this issue, for more details on the DNA mismatch repair pathway [233]). These insights were extended when it was shown that Msh3, but not Msh6, was also essential for the somatic expansion of CAG•CTG repeat expansions, directly implicating the MSH2/MSH3 MutSBeta complex [234].…”

Section: The Drivers Of Instability: Somatic Expansion Is Cell-divisimentioning

confidence: 99%

“…Cell division-independent inappropriate DNA mismatch repair has thus come to the fore as a likely mechanism of expansion of CAG•CTG repeats [238]. Along with other in vitro experiments, these animal model studies were critical in establishing the key players in the expansion pathway (for more details, see Wheeler and Dion, and Iyer and Pluciennik, in this issue [169,233]). However, in most cases, these studies did not lead directly to insights into the accrual of somatic expansions in mediating pathology (although see below).…”

Section: The Drivers Of Instability: Somatic Expansion Is Cell-divisimentioning

confidence: 99%

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Monckton

2021

JHD

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The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

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DNA Mismatch Repair and its Role in Huntington’s Disease

Cited by 65 publications

References 225 publications

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

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