The Repeat Expansion Diseases: The dark side of DNA repair

Zhao, Xiao-Nan; Usdin, Karen

doi:10.1016/j.dnarep.2015.04.019

Cited by 54 publications

(55 citation statements)

References 162 publications

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“…Specifically, the CGG repeats can form a number of different structures, like hairpins/stem loops, during DNA replication and somehow be responsible for the expansion. A variety of proteins involved in DNA repair and recombination are also likely to be involved in the process of repeat expansion [40].…”

Section: Discussionmentioning

confidence: 99%

“…The long patch BER has been suggested as the crucial pathway for DNA repair and large repeat expansions, which involve DNA repair polymerase β (Polβ), Polδ, and Polε [42]. CGG repeat could also arise by a hairpin structure formation on the displaced strand within 5' flap and ligation of this hairpin to the next Okazaki fragment repeated during replication cycles causing large expansion [40,43].…”

Section: Discussionmentioning

confidence: 99%

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Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

et al. 2015

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Fragile X syndrome (FXS) is mainly caused by an expansion of a cytosine-guanine-guanine (CGG) trinucleotide repeat (greater than 200) in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene resulting in gene silencing, methylation, and absence of FMRP. FXS involves a wide spectrum of phenotypes including intellectual disabilities, autism spectrum disorder (ASD), maladaptive behaviors or symptoms, social anxiety, mood disorders and physical features. Carriers of premutation alleles (55 -200 CGG repeats) can manifest with neurodevelopmental phenotypes and are at risk for the neurodegenerative fragile X-associated tremor/ataxia syndrome (FX-TAS) and about 20% of women with a premutation develop fragile Xassociated primary ovarian insufficiency (FXPOI). These phenotypes are believed to be caused by a distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Premutation alleles are unstable and depending on the CGG length and the presence of AGG interruptions have the potential to expand to larger premutation or full mutation alleles during transmission from mothers to their children. The contraction of a CGG repeat allele, although rare, has been observed. Here, we report the case of a three-generation family, who was identified as part of a pilot study of newborn screening for FXS. Specifically, the maternal grandmother carried a premutation allele (109 CGG repeats), which contracted to an intermediate size allele (52 CGG repeats) in her son, the father of a newborn girl (proband). This allele expanded to a premutation allele of 59 CGG repeats in the proband newborn. A premutation allele of 61 CGG repeats was detected in the proband's sister who demonstrated social phobia but normal cognition. The proband newborn showed some fragile X associated physical stigmata but normal cognition. Intriguingly, all FMR1 CGG expanded allele showed no AGG interruptions. This case shows a remarkable instability of premutation alleles throughout the three generations likely arising from different mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

et al. 2015

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“…During somatic expansion, the daughter strand of DNA is replicated with the CAG repeats, and the repeat expansion cycle can continue during subsequent rounds (149). The implications for this model go beyond HD, as CAG repeats alone are responsible for many other diseases including: dentatorubral-pallidolyusian atrophy, spinal and bulbar muscular atrophy, and forms of spinocerebellar ataxia’s (151). Similar to CAG repeats, CTG repeats also cause a host of disorders, depending on where in the genome the repeat occurs.…”

Section: Ber and Human Diseasementioning

confidence: 99%

Base excision repair of oxidative DNA damage from mechanism to disease

Freudenthal¹

2017

Front Biosci

172

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Reactive oxygen species continuously assault the structure of DNA resulting in oxidation and fragmentation of the nucleobases. Both oxidative DNA damage itself and its repair mediate the progression of many prevalent human maladies. The major pathway tasked with removal of oxidative DNA damage, and hence maintaining genomic integrity, is base excision repair (BER). The aphorism that structure often dictates function has proven true, as numerous recent structural biology studies have aided in clarifying the molecular mechanisms used by key BER enzymes during the repair of damaged DNA. This review focuses on the mechanistic details of the individual BER enzymes and the association of these enzymes during the development and progression of human diseases, including cancer and neurological diseases. Expanding on these structural and biochemical studies to further clarify still elusive BER mechanisms, and focusing our efforts toward gaining an improved appreciation of how these enzymes form co-complexes to facilitate DNA repair is a crucial next step toward understanding how BER contributes to human maladies and how it can be manipulated to alter patient outcomes. KeywordsBase excision repair; Oxidative DNA damage; DNA repair; Review INTRODUCTION Oxidative DNA damageReactive oxygen species (ROS) are generated as a by-product of normal mitochondrial activity, these include superoxide, hydrogen peroxide, and the hydroxyl radical. The metabolic processes that generate ROS are essential for the cell, however a tradeoff is involved, and if not properly controlled the ROS concentration can exceed the antioxidant scavenging ability of the cell. Under this cellular condition, termed oxidative stress, ROS can cause extensive damage to cellular macromolecules. The structure of DNA is especially vulnerable to damage, and it has been estimated that DNA damage occurs at a rate of 10 4 Send correspondence to: Bret D. Freudenthal, 4015 WHW, Laboratory of Genome Maintenance and Structural Biology, Department of Biochemistry Molecular Biology, and Department of Cancer Biology, University of Kansas Medical Center Kansas, 66160, bfreudenthal@kumc.edu. HHS Public AccessAuthor manuscript Front Biosci (Landmark Ed). Author manuscript; available in PMC 2017 August 23. Published in final edited form as:Front Biosci (Landmark Ed). ; 22: 1493-1522. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript lesions/cell/day in humans, with oxidative DNA damage being particularly prevalent (1). Specifically, the structures of all four DNA nucleobases are susceptible to oxidative damage from ROS, with more than 100 different types of base damage being identified as products of oxidative stress (2). This base damage includes fragmented or ring-opened forms and oxidized aromatic derivatives. Several base lesions are highlighted in Figure 1 and discussed in more detail below. Generally, when the nucleobase structure is altered as the result of oxidative damage, its base-pairing properties are also altered, often leading to either...

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“…Since then, simple repeat sequence expansions have been associated with over twenty more neurological disorders [166, 300, 333] (Table 1). What has been learned is that microsatellite expansions may cause disease in multiple ways.…”

Section: Introductionmentioning

confidence: 99%

RNA biology of disease-associated microsatellite repeat expansions

Rohilla

Gagnon

2017

acta neuropathol commun

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Microsatellites, or simple tandem repeat sequences, occur naturally in the human genome and have important roles in genome evolution and function. However, the expansion of microsatellites is associated with over two dozen neurological diseases. A common denominator among the majority of these disorders is the expression of expanded tandem repeat-containing RNA, referred to as xtrRNA in this review, which can mediate molecular disease pathology in multiple ways. This review focuses on the potential impact that simple tandem repeat expansions can have on the biology and metabolism of RNA that contain them and underscores important gaps in understanding. Merging the molecular biology of repeat expansion disorders with the current understanding of RNA biology, including splicing, transcription, transport, turnover and translation, will help clarify mechanisms of disease and improve therapeutic development.

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The Repeat Expansion Diseases: The dark side of DNA repair

Cited by 54 publications

References 162 publications

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

Base excision repair of oxidative DNA damage from mechanism to disease

RNA biology of disease-associated microsatellite repeat expansions

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