Tissue specificity in DNA repair: lessons from trinucleotide repeat instability

Dion, Vincent

doi:10.1016/j.tig.2014.04.005

Cited by 42 publications

(39 citation statements)

References 108 publications

(161 reference statements)

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“…In addition to intergenerational expansions, significant instability in somatic tissues can be seen in some TNR diseases, which can contribute to disease progression (for reviews see Dion, 2014; Lopez Castel et al ., 2010; Pearson et al ., 2005)). For example, in human HD patients, dramatic expansions (gains of up to 1000 repeats) are observed in striatal cells, the brain region most affected by the disease (Kennedy et al ., 2003).…”

Section: Repeat Expansions Cause Human Diseasementioning

confidence: 99%

Repeat instability during DNA repair: Insights from model systems

Usdin

House

Freudenreich

2015

Critical Reviews in Biochemistry and Molecular Biology

167

218

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The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them.

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Section: Repeat Expansions Cause Human Diseasementioning

confidence: 99%

Repeat instability during DNA repair: Insights from model systems

Usdin

House

Freudenreich

2015

Critical Reviews in Biochemistry and Molecular Biology

167

218

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“…CAG repeat expansions are at the root of several neurodegenerative and neuromuscular diseases, such as Huntington's disease (HD), various spinocerebellar ataxias (SCAs), and myotonic dystrophy (DM1) McMurray 2010). The expansion and contraction of triplet repeats occur in both germline and somatic tissues, leading to variable degrees of penetrance of the disease phenotype Dion 2014). Appropriate repair of CAG repeat-induced damage is vital to the cell, as proper repair can prevent further expansion and aggravation of the disease (McMurray 2010; Usdin et al 2015).…”

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confidence: 99%

Regulation of recombination at yeast nuclear pores controls repair and triplet repeat stability

et al. 2015

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Secondary structure-forming DNA sequences such as CAG repeats interfere with replication and repair, provoking fork stalling, chromosome fragility, and recombination. In budding yeast, we found that expanded CAG repeats are more likely than unexpanded repeats to localize to the nuclear periphery. This positioning is transient, occurs in late S phase, requires replication, and is associated with decreased subnuclear mobility of the locus. In contrast to persistent double-stranded breaks, expanded CAG repeats at the nuclear envelope associate with pores but not with the inner nuclear membrane protein Mps3. Relocation requires Nup84 and the Slx5/8 SUMO-dependent ubiquitin ligase but not Rad51, Mec1, or Tel1. Importantly, the presence of the Nup84 pore subcomplex and Slx5/8 suppresses CAG repeat fragility and instability. Repeat instability in nup84, slx5, or slx8 mutant cells arises through aberrant homologous recombination and is distinct from instability arising from the loss of ligase 4-dependent end-joining. Genetic and physical analysis of Rad52 sumoylation and binding at the CAG tract suggests that Slx5/8 targets sumoylated Rad52 for degradation at the pore to facilitate recovery from acute replication stress by promoting replication fork restart. We thereby confirmed that the relocation of damage to nuclear pores plays an important role in a naturally occurring repair process.

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“…Different expression levels of MSH3 and MLH3 have been identified in mouse strains that exhibit different expansion frequencies supporting that the level of DNA repair proteins might be correlated with the degree of CAG repeat instability. Other studies also support a role for the stochiometries of DNA repair proteins in CAG repeat instability [4,64,[71][72][73]. Few data have reported the role of genetic factors in CAG repeat contractions mainly observed in HD maternal transmissions and only Csb has been reported to promote contractions in paternal transmissions.…”

Section: Genetic Modifiers Of Somatic Mosaicismmentioning

confidence: 90%

“…In HD patients, the pathogenic allele contains more than 40 repeats and becomes highly unstable and usually increases in size in successive generations (intergenerational instability) and in somatic tissues (somatic instability). Longer expanded alleles are associated with more severe forms of disease and result in a decreasing age of onset from one generation to the next [1,3,4]. Among trinucleotide repeat disorders, HD disease is the fourth reported.…”

Section: Introductionmentioning

confidence: 99%

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

Dandelot¹,

Tomé²

2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose characterstics were first described by George Huntington in 1872. Several decades later, in 1993, the mutation behind this disease was found to be an unstable expanded CAG repeat within exon 1 of the HTT gene localized on the short arm of chromosome 4. The majority of HD patients carry more than 40 CAG repeats, which become unstable and usually increase in size in successive generations and in tissues. In order to dissect the molecular mechanisms underlying CAG repeat instability, several HD mouse models have been created in the 1990s. Significant data have revealed that the absence of proteins from the mismatch repair (MMR) or the base and nucleotide excision repair decreased the pathogenic expansion-biased somatic mosaicism and/or intergenerational expansions. Some polymorphic variants of MMR genes have also been associated with reduced somatic expansions. Since expansionbiased somatic mosaicism likely contributes to disease manifestations, these results suggest that genetic modifiers of instability may also affect disease severity. In this chapter, we provide an overview of the data recently published about DNA instability; the roles of genetic modifiers of trinucleotide repeat dynamics in mouse models; and the possible therapeutic interventions.

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Tissue specificity in DNA repair: lessons from trinucleotide repeat instability

Cited by 42 publications

References 108 publications

Repeat instability during DNA repair: Insights from model systems

Repeat instability during DNA repair: Insights from model systems

Regulation of recombination at yeast nuclear pores controls repair and triplet repeat stability

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

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