Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation

Gerhardt, Jeannine; Zaninović, Nikica; Zhan, Qiansheng; Madireddy, Advaitha; Nolin, Sarah L.; Ersalesi, Nicole; Yan, Zi; Rosenwaks, Zev; Schildkraut, Carl L.

doi:10.1083/jcb.201404157

Cited by 46 publications

(33 citation statements)

References 59 publications

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“…In FRDA cells, however, the majority of replication forks progress only in the 3’−5’ direction, originating from initiation sites downstream of the GAA repeats. A similar phenomenon of unidirectional fork movement through the CGG repeats at the FMR1 locus was observed in FXS hESCs (Gerhardt et al, 2014a; Gerhardt et al, 2014b). However, inactivation of a replication origin upstream of the expanded CGG repeats by a point mutation was required to elicit the alteration in replication fork direction in FXS hESCs.…”

Section: Discussionsupporting

confidence: 65%

“…We examined the DNA replication program in FRDA patient cells to determine if defects in DNA replication processes cause GAA repeat expansions. We found that replication fork progression at the FXN gene is altered in FRDA cells to a much greater extent than the replication impediment we previously detected at the FMR1 locus in unaffected and FXS human embryonic stem cells (hESCs) using SMARD (Gerhardt et al, 2014a; Gerhardt et al, 2014b). The major stall detected in FRDA cells suggests that the replication fork indeed encounters a block imposed by stable non-canonical DNA structures (e.g.…”

Section: Discussionmentioning

confidence: 59%

“…Additionally, repeat expansion takes place solely at the disease locus indicating that specific cis -elements are crucial for the mechanism. Therefore, the length of the repeat tract together with activation or inactivation of local replication origins, which alter fork progression, are the primary determinants of the repeat expansion (Gerhardt et al, 2014b). These cis -elements accompanied by the activities of trans -factors, such as mismatch repair protein Msh2, facilitate GAA repeat expansions (Du et al, 2012; Ku et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

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Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells

et al. 2016

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SUMMARY Friedreich's ataxia (FRDA) is caused by the expansion of GAA repeats located in the Frataxin (FXN) gene. The GAA repeats continue to expand in FRDA patients, aggravating symptoms and contributing to disease progression. The mechanism leading to repeats expansion and decreased FXN transcription remains unclear. Using single molecule analysis of replicated DNA, we detected that expanded GAA repeats present a substantial obstacle for the replication machinery at the FXN locus in FRDA cells. Furthermore, aberrant origin activation and lack of a proper stress response to rescue the stalled forks in FRDA cells causes an increase in 3’−5’ progressing forks, which could enhance repeat expansion and hinder FXN transcription by head-on collision with RNA polymerases. Treatment of FRDA cells with GAA-specific polyamides rescue DNA replication forks stalling and alleviate expansion of the GAA repeats, implicating DNA triplexes as a replication impediment, and suggesting that fork stalling might be a therapeutic target for FRDA.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 99%

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Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells

et al. 2016

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“…Indeed, recent data on the replication patterns at the DM1 and FMR1 loci in human cells shows evidence for changes in origin usage at unstable alleles (Cleary et al ., 2010; Gerhardt et al ., 2014a; Mirkin & Mirkin, 2014). At the FMR1 locus, a common SNP identified in one of the flanking origins has been shown to be associated with an expansion-prone haplotype (Gerhardt et al ., 2014b). …”

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

164

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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“…The postulated “rapid path” expansion mechanism is likely more complex and could involve a cis -acting modifier of repeat length stability, a candidate for which has been identified 53 kb proximal to the repeat [36,37]. …”

Section: Factors Affecting Stability and Expansion Of The Cgg/agg mentioning

confidence: 99%

Development of Genetic Testing for Fragile X Syndrome and Associated Disorders, and Estimates of the Prevalence of FMR1 Expansion Mutations

Macpherson

2016

Genes

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The identification of a trinucleotide (CGG) expansion as the chief mechanism of mutation in Fragile X syndrome in 1991 heralded a new chapter in molecular diagnostic genetics and generated a new perspective on mutational mechanisms in human genetic disease, which rapidly became a central paradigm (“dynamic mutation”) as more and more of the common hereditary neurodevelopmental disorders were ascribed to this novel class of mutation. The progressive expansion of a CGG repeat in the FMR1 gene from “premutation” to “full mutation” provided an explanation for the “Sherman paradox,” just as similar expansion mechanisms in other genes explained the phenomenon of “anticipation” in their pathogenesis. Later, FMR1 premutations were unexpectedly found associated with two other distinct phenotypes: primary ovarian insufficiency and tremor-ataxia syndrome. This review will provide a historical perspective on procedures for testing and reporting of Fragile X syndrome and associated disorders, and the population genetics of FMR1 expansions, including estimates of prevalence and the influence of AGG interspersions on the rate and probability of expansion.

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Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation

Abstract: An SNP upstream of the CGG repeats located at a replication initiation site may contribute to origin inactivation, to altered replication fork progression through the CGG repeats, and repeat expansion to fragile X full mutation.

Cited by 46 publications

References 59 publications

Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells

Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells

Repeat instability during DNA repair: Insights from model systems

Development of Genetic Testing for Fragile X Syndrome and Associated Disorders, and Estimates of the Prevalence of FMR1 Expansion Mutations

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