Chemical modifiers of unstable expanded simple sequence repeats: What goes up, could come down

Gomes‐Pereira, Mário; Monckton, Darren G.

doi:10.1016/j.mrfmmm.2006.01.011

Cited by 64 publications

(87 citation statements)

References 160 publications

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“…As we have shown here, cleavage by zfGCT exhibits a significant length dependence that should help focus its activity on expanded repeats. Treatments that can promote the reduction of large CAG repeat tracts, or interrupt them, might form the basis for a future therapeutic approach designed to prevent or delay the onset of late-stage neurological disorders caused by expanded CAG repeat tracts (46).…”

Section: Discussionmentioning

confidence: 99%

Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells

Mittelman

Moye²,

Morton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Expanded triplet repeats have been identified as the genetic basis for a growing number of neurological and skeletal disorders. To examine the contribution of double-strand break repair to CAG⅐CTG repeat instability in mammalian systems, we developed zinc finger nucleases (ZFNs) that recognize and cleave CAG repeat sequences. Engineered ZFNs use a tandem array of zinc fingers, fused to the FokI DNA cleavage domain, to direct double-strand breaks (DSBs) in a site-specific manner. We first determined that the ZFNs cleave CAG repeats in vitro. Then, using our previously described tissue culture assay for identifying modifiers of CAG repeat instability, we found that transfection of ZFN-expression vectors induced up to a 15-fold increase in changes to the CAG repeat in human and rodent cell lines, and that longer repeats were much more sensitive to cleavage than shorter ones. Analysis of individual colonies arising after treatment revealed a spectrum of events consistent with ZFN-induced DSBs and dominated by repeat contractions. We also found that expressing a dominant-negative form of RAD51 in combination with a ZFN, dramatically reduced the effect of the nuclease, suggesting that DSB-induced repeat instability is mediated, in part, through homology directed repair. These studies identify a ZFN as a useful reagent for characterizing the effects of DSBs on CAG repeats in cells.DNA repair ͉ gene targeting ͉ triplet repeat instability ͉ zinc finger nucleases

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Section: Discussionmentioning

confidence: 99%

Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells

Mittelman

Moye²,

Morton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In HD, somatic instability is expansion‐biased and age‐ dependent, with larger tracts more susceptible to expansion 11, 12. It occurs in postmitotic neurons and is prominent in striatum and cortex, tissues particularly affected in HD 13.…”

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confidence: 99%

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

193

186

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ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990

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“…Therefore, the possibility of genetic confounders could not be excluded. For example, size of the repeat locus (7-9), cis-and trans-elements (8, 10, 11) and genetic background (8,12,13) can all affect mutation frequency. The mean spontaneous ESTR mutation frequency was elevated in these outbred mice relative to other inbred strains [Ϸ2X greater than typical (3)].…”

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confidence: 99%

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

Yauk¹,

Polyzos²,

Rowan-Carroll³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

274

202

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Particulate air pollution is widespread, yet we have little understanding of the long-term health implications associated with exposure. We investigated DNA damage, mutation, and methylation in gametes of male mice exposed to particulate air pollution in an industrial/ urban environment. C57BL/CBA mice were exposed in situ to ambient air near two integrated steel mills and a major highway, alongside control mice breathing high-efficiency air particulate (HEPA) filtered ambient air. PCR analysis of an expanded simple tandem repeat (ESTR) locus revealed a 1.6-fold increase in sperm mutation frequency in mice exposed to ambient air for 10 wks, followed by a 6-wk break, compared with HEPA-filtered air, indicating that mutations were induced in spermatogonial stem cells. DNA collected after 3 or 10 wks of exposure did not exhibit increased mutation frequency. Bulky DNA adducts were below the detection threshold in testes samples, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated at 3 and 10 wks, possibly resulting from oxidative stress arising from exposure to particles and associated airborne pollutants. Sperm DNA was hypermethylated in mice breathing ambient relative to HEPAfiltered air and this change persisted following removal from the environmental exposure. Increased germ-line DNA mutation frequencies may cause population-level changes in genetic composition and disease. Changes in methylation can have widespread repercussions for chromatin structure, gene expression and genome stability. Potential health effects warrant extensive further investigation.DNA adducts ͉ DNA strand breaks ͉ tandem repeat mutation C ombustion of fossil fuels results in the production of complex mixtures of chemicals that are released into the environment and potentially affect millions of people globally. Previous work demonstrated that the offspring of wild birds breeding near integrated steel mills on the North American Great Lakes inherited increased numbers of tandem repeat DNA sequence mutations compared with those from areas without steel mills (1, 2). Subsequent studies investigated expanded simple tandem repeat (ESTR) mutation in outbred laboratory mice caged near two integrated steel mills and a major highway in Hamilton, Ontario, Canada, and at a rural reference site (3, 4). Using a pedigree approach (5), a significant increase in germ-line mutation rate was found in mice housed in the industrial environment compared with the reference site. The majority of mutations were transmitted through the paternal germ line. High-efficiency particulate-air (HEPA) filtration of the ambient air resulted in a significant reduction in mutation frequency, down to levels measured at the reference location (4). Therefore, the particulate fraction of air in this industrial location was largely responsible for the mutagenic hazard.These findings show that chemical pollutants may cause heritable mutation. Further research is required to confirm these results...

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Chemical modifiers of unstable expanded simple sequence repeats: What goes up, could come down

Cited by 64 publications

References 160 publications

Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells

Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

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