Quantitative Evaluation of Toxic Polyglycine Biosynthesis and Aggregation in Cell Models Expressing Expanded CGG Repeats

Derbis, Magdalena; Konieczny, Patryk; Walczak, Agnieszka; Sekrecki, Michał; Sobczak, Krzysztof

doi:10.3389/fgene.2018.00216

Cited by 9 publications

(21 citation statements)

References 42 publications

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“…FMRP protein has been shown to be one of the leading causes of the fragile X syndrome (Zhang et al , ) as well as one of the leading causes of monogenetic forms of autism (Bassell & Warren, ; Hernandez et al , ). In addition to aggregating in diseases (Sjekloća et al , ; Derbis et al , ), FMRP is a known quadruplex‐binding protein (Zhang et al , ; Vasilyev et al , ). Future studies on whether these roles are related would be of significant interest.…”

Section: Discussionmentioning

confidence: 99%

G‐Quadruplexes act as sequence‐dependent protein chaperones

et al. 2020

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Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent protein aggregation more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences' effects on protein aggregation, we show that the holdase chaperone effect of nucleic acids is sequence-dependent. G-Quadruplexes prevent protein aggregation via quadruplex:protein oligomerization. They also increase the folded protein level of a biosensor in E. coli. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as fragile X and amyotrophic lateral sclerosis (ALS), and provide evidence that nucleic acids have the ability to modulate the folding environment of E. coli.

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Section: Discussionmentioning

confidence: 99%

G‐Quadruplexes act as sequence‐dependent protein chaperones

et al. 2020

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“…FMRP protein has been shown to be one of the leading causes of the fragile X syndrome (17) as well as one of the leading causes of monogenetic forms of autism (31,32). In addition to aggregating in disease (33,34), FMRP is a known quadruplex-binding protein (16,17). Future studies on whether these roles are related would be of significant interest.…”

Section: Discussionmentioning

confidence: 99%

G-Quadruplexes Act as Sequence Dependent Chaperones via Protein Oligomerization

Begeman

Litberg

Bourne

et al. 2019

Preprint

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Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent aggregation up to 300-fold more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences' effects on aggregation, we demonstrate that the holdase chaperone effect of nucleic acids is highly sequence dependent. Quadruplexes are found to have especially potent effects on aggregation with many different proteins via quadruplex:protein oligomerization. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as Fragile X and Amyotrophic lateral sclerosis (ALS). Main Text:Chaperones are a diverse group of proteins and other molecules that regulate proteostasis (1) in the cell by preventing protein aggregation (holdases) and helping protein folding (foldases). Recently, molecules other than traditional protein chaperones have been shown to play important roles in these processes (2, 3). We recently showed that nucleic acids can possess potent holdase activity, with the best sequences having higher holdase activity than any previously characterized chaperone (4). Nucleic acids can also collaborate with Hsp70 to help protein folding, acting similarly to small heat shock proteins (4-7). Nucleic acids can also bring misfolded proteins to stress granules (8), and are a primary component of the nucleolus, which was recently shown to store misfolded proteins under stress conditions (9). However, the structural characteristics, sequence dependence, and mechanistic understanding of how nucleic acids act as chaperones remains unclear.A critical question in understanding the holdase activity of nucleic acids is whether this activity is sequence specific? Previously, we showed that polyA, polyT, polyG, and polyC prevented aggregation with varying kinetics, suggesting that sequence specificity was possible (4). Here, we test sequence specificity by examining over 500 nucleic acids of varying sequence for

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“…We overexpressed a 100×CGG construct carrying the 5′UTR sequence of the FMR1 gene containing ~100 CGG repeats (Fig. 2a ; artificial FXTAS model) 19 , 23 . RAN translation of mRNA from this construct leads to the biosynthesis of FMRpolyG fused with GFP (FMRpolyG-GFP).…”

Section: Resultsmentioning

confidence: 99%

“…In an FXTAS cell model, some RNA-binding compounds reduced SAM68-dependent aberrant splicing and inhibited RAN translation of FMRpolyG 20 – 22 . In a similar cell model, we showed that antisense oligonucleotides (ASOs) complementary to the FMR1 -specific sequence downstream of the CGG repeat tract induced targeted mRNA degradation through RNase H1 recruitment and caused a significant decrease in FMRpolyG production and aggregation 23 . Recently, ASOs targeting RAN translation initiation site on mRNA was also proved to reduce biosynthesis of FMRpolyG in FXTAS cellular models 24 .…”

Section: Introductionmentioning

confidence: 99%

Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats

et al. 2021

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.

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Quantitative Evaluation of Toxic Polyglycine Biosynthesis and Aggregation in Cell Models Expressing Expanded CGG Repeats

Cited by 9 publications

References 42 publications

G‐Quadruplexes act as sequence‐dependent protein chaperones

G‐Quadruplexes act as sequence‐dependent protein chaperones

G-Quadruplexes Act as Sequence Dependent Chaperones via Protein Oligomerization

Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats

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