Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans

Qawasmi, Lena; Braun, Maya; Guberman, Irene; Cohen, Emiliano; Naddaf, Lamis; Mellul, Anna; Matilainen, Olli; Roitenberg, Noa; Share, Danielle; Stupp, Doron; Chahine, Haya; Cohen, Ehud; Garcia, Susana M. D. A.; Tabach, Yuval

doi:10.1016/j.jmb.2019.03.003

Cited by 12 publications

(35 citation statements)

References 36 publications

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“…This further substantiates its potential as a drug candidate for targeting CAG RNA toxicity in polyQ diseases. An in vivo gene silencing effect has also been reported to be associated with expanded CUG RNA toxicity (47). In addition to rescuing cellular proteins that are recruited to RNA foci, it should be noted that small molecules that target CUG repeat RNAs (30) may mediate phenotypic suppression by promoting the formation of CUG homoduplexes in cells.…”

Section: Discussionmentioning

confidence: 99%

CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration

Peng

Guo

Lin

et al. 2021

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

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DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington’s disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the Nudix hydrolase 16 (NUDT16) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing NUDT16 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of NUDT16 and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent NUDT16 silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.

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Section: Discussionmentioning

confidence: 99%

CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration

Peng

Guo

Lin

et al. 2021

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

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“…The toxicity of expanded RNA repeats is likely associated with their ability to fold into unusual RNA secondary structures. The list of known repetitive RNAs with confirmed toxicity includes CUG, CCUG, CGG, CAG, AUUCU, UGGAA, AUUUC, GGCCUG, and GGGGCC repeats (22, [85][86][87][88][89][90][91][92][93][94].…”

Section: Toxic Gain Of Function At the Level Of Rnamentioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

216

239

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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“…To reconfirm the robustness of the model, we quantified the baseline toxicity of the expanded repeats 47 . We conducted a motility assay and measured the speed of movement of the nematodes using video recording under light microscopy at three different ages (2 nd , 4 th , and 6 th day of adulthood).…”

Section: In Vivo Isogenic Model For Studying Phenotypes Of Long Rna Repeatsmentioning

confidence: 99%

“…The RNAi machinery is also associated with various pathological states [44][45][46] . Specifically, it was found to contribute to the aberrant activation of pathogenic RNA toxicity mechanisms in nematodes 47 , drosophila 48 , and mammals [49][50][51] . Expanded DNA repeats, when transcribed, tend to form stable hairpins that accumulate as RNA foci in the nucleus and cytoplasm 4,[52][53][54] .…”

Section: Introductionmentioning

confidence: 99%

RNA interference mediates RNA toxicity with parent-of-origin effects inC. elegansexpressing CTG repeats

Braun

Shoshani

Teixeira

et al. 2021

Preprint

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Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases. These repeats cause RNA toxicity and trigger multisystemic symptoms that worsen with age. RNA toxicity can trigger, through an unclear mechanism, severe disease manifestation in infants that inherited repeats from their mothers. Here we show in Caenorhabditis elegans how RNA interference machinery causes intergenerational toxicity through inheritance of siRNAs derived from CUG repeats. The maternal repeat-derived small RNAs cause transcriptomic changes in the offspring, reduce motility and shorten lifespan. However, the toxicity phenotypes in the offspring can be rescued by perturbing the RNAi machinery in affected mothers. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring and causes disease phenotypes through intergenerational epigenetic inheritance.

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Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans

Cited by 12 publications

References 36 publications

CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration

CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

RNA interference mediates RNA toxicity with parent-of-origin effects inC. elegansexpressing CTG repeats

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