Trinucleotide Repeat Expansion Diseases, RNAi, and Cancer

Murmann, Andrea E.; Yu, Jindan; Opal, Puneet; Peter, Marcus E.

doi:10.1016/j.trecan.2018.08.004

Cited by 22 publications

(18 citation statements)

References 151 publications

(202 reference statements)

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“…CAG-repeat-containing mRNAs have been shown to induce sRNA formation and cellular toxicity via RNAi ( Bañez-Coronel et al, 2012 ). However, we recently reported that these sCAGs likely target fully complementary CUG containing repeat regions in the ORFs of genes critical for cell survival in an siRNA-like mechanism ( Murmann et al, 2018a ; Murmann et al, 2018b ).…”

Section: Discussionmentioning

confidence: 99%

CD95/Fas ligand mRNA is toxic to cells

Putzbach

Haluck-Kangas

Gao

et al. 2018

eLife

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CD95/Fas ligand binds to the death receptor CD95 to induce apoptosis in sensitive cells. We previously reported that CD95L mRNA is enriched in sequences that, when converted to si/shRNAs, kill all cancer cells by targeting critical survival genes (Putzbach et al., 2017). We now report expression of full-length CD95L mRNA itself is highly toxic to cells and induces a similar form of cell death. We demonstrate that small (s)RNAs derived from CD95L are loaded into the RNA induced silencing complex (RISC) which is required for the toxicity and processing of CD95L mRNA into sRNAs is independent of both Dicer and Drosha. We provide evidence that in addition to the CD95L transgene a number of endogenous protein coding genes involved in regulating protein translation, particularly under low miRNA conditions, can be processed to sRNAs and loaded into the RISC suggesting a new level of cell fate regulation involving RNAi.

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Section: Discussionmentioning

confidence: 99%

CD95/Fas ligand mRNA is toxic to cells

Putzbach

Haluck-Kangas

Gao

et al. 2018

eLife

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“…They occasionally induce genomic instability leading to generation of SVs, including both pathogenic and adaptive copy number variations (CNVs). The most famous disease related to CNV of tandem repeats is triplet repeat disease, which is evoked by the expansion of arrays comprised of very short units, such as CAG, GAA, CGG, and CCG trinucleotides ( 7 ). In contrast, facioscapulohumeral muscular dystrophy is caused by the contraction of D4Z4 macrosatellite repeats comprised of a 3.3-kb unit harboring the DUX4 gene ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Catalytically inactive Cas9 impairs DNA replication fork progression to induce focal genomic instability

Doi

Okada

Yasukawa

et al. 2021

Nucleic Acids Research

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Catalytically inactive Cas9 (dCas9) has become an increasingly popular tool for targeted gene activation/inactivation, live-cell imaging, and base editing. While dCas9 was reported to induce base substitutions and indels, it has not been associated with structural variations. Here, we show that dCas9 impedes replication fork progression to destabilize tandem repeats in budding yeast. When targeted to the CUP1 array comprising ∼16 repeat units, dCas9 induced its contraction in most cells, especially in the presence of nicotinamide. Replication intermediate analysis demonstrated replication fork stalling in the vicinity of dCas9-bound sites. Genetic analysis indicated that while destabilization is counteracted by the replisome progression complex components Ctf4 and Mrc1 and the accessory helicase Rrm3, it involves single-strand annealing by the recombination proteins Rad52 and Rad59. Although dCas9-mediated replication fork stalling is a potential risk in conventional applications, it may serve as a novel tool for both mechanistic studies and manipulation of genomic instability.

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“…Essentially, they serve as genetic fingerprints; a consequence of their high mutation rate. In addition, microsatellites have a well-established role in diseases such as fragile X syndrome, spinocerebellar ataxias, myotonic dystrophy, Friedrich ataxia, and Huntington's disease [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Abundance of ethnically biased microsatellites in human gene regions

et al. 2019

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Microsatellites–a type of short tandem repeat (STR)–have been used for decades as putatively neutral markers to study the genetic structure of diverse human populations. However, recent studies have demonstrated that some microsatellites contribute to gene expression, cis heritability, and phenotype. As a corollary, some microsatellites may contribute to differential gene expression and RNA/protein structure stability in distinct human populations. To test this hypothesis, we investigate genotype frequencies, functional relevance, and adaptive potential of microsatellites in five super-populations (ethnicities) drawn from the 1000 Genomes Project. We discover 3,984 ethnically-biased microsatellite loci (EBML); for each EBML at least one ethnicity has genotype frequencies statistically different from the remaining four. South Asian, East Asian, European, and American EBML show significant overlap; on the contrary, the set of African EBML is mostly unique. We cross-reference the 3,984 EBML with 2,060 previously identified expression STRs (eSTRs); repeats known to affect gene expression (64 total) are over-represented. The most significant pathway enrichments are those associated with the matrisome: a broad collection of genes encoding the extracellular matrix and its associated proteins. At least 14 of the EBML have established links to human disease. Analysis of the 3,984 EBML with respect to known selective sweep regions in the genome shows that allelic variation in some of them is likely associated with adaptive evolution.

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Trinucleotide Repeat Expansion Diseases, RNAi, and Cancer

Cited by 22 publications

References 151 publications

CD95/Fas ligand mRNA is toxic to cells

CD95/Fas ligand mRNA is toxic to cells

Catalytically inactive Cas9 impairs DNA replication fork progression to induce focal genomic instability

Abundance of ethnically biased microsatellites in human gene regions

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