Expansion of GAA triplet repeats in the human genome: unique origin of the FRDA mutation at the center of an Alu

Clark, Rhonda M.; Dalgliesh, Gillian L.; Endres, Dan; Gómez, María Mercedes; Taylor, Jim; Bidichandani, Sanjay I.

doi:10.1016/j.ygeno.2003.09.001

Cited by 42 publications

(45 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To test whether other TNR disease-derived sequences were toxic to cancer cells when introduced as siRNAs, the repeats siGAA/UUC (GAA is amplified in Friedreich's ataxia [22]), siCGG/CCG (CGG found in fragile X tremor ataxia syndrome [FXTAS] and CCG found in Fragile XE mental retardation [FRAXE] [1]) were transfected into HeyA8 (ovarian) and A549 (lung) cancer cells (Fig 2A).…”

Section: Identification Of the Most Toxic Tnr Based Sirnasmentioning

confidence: 99%

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Murmann

Gao

Putzbach

et al. 2018

Preprint

View full text Add to dashboard Cite

Synopsis Bullet points• CAG and CUG trinucleotide repeat (TNR) derived siRNAs are super toxic to cancer cells.• Super toxic siRNA duplexes kill cancer cells via RNAi by targeting survival genes with sequence complementarity.• Super toxic siRNAs reduce tumor growth in a murine cancer model without affecting normal tissues. Synopsis blurbTrinucleotide repeat disorders like Huntington's disease show severe neurological pathologies, but are also characterised by reduced cancer susceptibility. siRNAs based on trinucleotide repeats show specific toxicity against cancer cells, explaining the low cancer incidence in triple repeat diseases.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/247429 doi: bioRxiv preprint first posted online Jan. 12, 2018; peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/247429 doi: bioRxiv preprint first posted online Jan. 12, 2018; 2 Abstract Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complimentary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anti-cancer reagents.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/247429 doi: bioRxiv preprint first posted online Jan. 12, 2018; 3 IntroductionTrinucleotide repeat (TNR) expansions are the cause of a large number of degenerative disease syndromes characterized by amplification of DNA triplet motifs [1]. They include spinocerebellar ataxias (SCAs), spinobulbar muscular atrophy (SBMA), myotonic dystrophy type 1 (DM1), and Huntington's disease (HD) [1,2]. HD is a dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin (HTT) gene. It has been shown that the resulting glutamine expansions (polyQ) in HTT are toxic to cells [3,4] and that the length of the CAG amplifications determines severity and onset of the disease...

show abstract

Section: Identification Of the Most Toxic Tnr Based Sirnasmentioning

confidence: 99%

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Murmann

Gao

Putzbach

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

Section: ‫4מ‬mentioning

confidence: 99%

“…Local recombination rates might affect microsatellite mutation rates if some new length-variants originate through unequal crossing over or gene conversion (Ellegren 2004;Pearson et al 2005). Relatedly, microsatellites might be less stable if they are located within Alu repeats (Clark et al 2004) because these repeats are known to mediate recombination . Transcription can influence microsatellite mutation rates through alterations of DNA structure (Mochmann and Wells 2004;Pearson et al 2005) or interference with replication (Krasilnikova et al 1998).…”

Section: ‫4מ‬mentioning

confidence: 99%

“…Local recombination rates might affect microsatellite mutation rates if some new length-variants originate through unequal crossing over or gene conversion (Ellegren 2004;Pearson et al 2005). Relatedly, microsatellites might be less stable if they are located within Alu repeats (Clark et al 2004) (Krasilnikova et al 1998).If mutations at microsatellites result mostly from replication slippage in the germline, then microsatellites located on sex chromosomes and autosomes should have distinct mutation rates because of the different number of DNA replication rounds they undergo (Y > autosomes > X) (Li et al 2002). Clearly, the microsatellite mutation process is a function of inherent sequence properties as well as chromosomal and regional genomic factors.…”

mentioning

confidence: 99%

“…S2A; Table S2), (AAG) n has the highest mutability, while microsatellites with other motifs display more similar behaviors. Expansion of the (AAG) n microsatellite in frataxin causes Friedrich's ataxia (Pearson et al 2005); (AAG) n forms triplex DNA and is associated with Alu elements (Clark et al 2004). The genome-wide mutability of (AGC) n and (CCG) n , expansions of which at some loci also cause diseases (Pearson et al 2005), is similar to that of motifs not currently known to be associated with diseases ( Fig.…”

mentioning

confidence: 99%

See 2 more Smart Citations

The genome-wide determinants of human and chimpanzee microsatellite evolution

Kelkar¹,

Tyekucheva²,

Chiaromonte³

et al. 2007

Genome Res.

237

250

View full text Add to dashboard Cite

Mutation rates of microsatellites vary greatly among loci. The causes of this heterogeneity remain largely enigmatic yet are crucial for understanding numerous human neurological diseases and genetic instability in cancer. In this first genome-wide study, the relative contributions of intrinsic features and regional genomic factors to the variation in mutability among orthologous human-chimpanzee microsatellites are investigated with resampling and regression techniques. As a result, we uncover the intricacies of microsatellite mutagenesis as follows. First, intrinsic features (repeat number, length, and motif size), which all influence the probability and rate of slippage, are the strongest predictors of mutability. Second, mutability increases nonuniformly with length, suggesting that processes additional to slippage, such as faulty repair, contribute to mutations. Third, mutability varies among microsatellites with different motif composition likely due to dissimilarities in secondary DNA structure formed by their slippage intermediates. Fourth, mutability of mononucleotide microsatellites is impacted by their location on sex chromosomes vs. autosomes and inside vs. outside of Alu repeats, the former confirming the importance of replication and the latter suggesting a role for gene conversion. Fifth, transcription status and location in a particular isochore do not influence microsatellite mutability. Sixth, compared with intrinsic features, regional genomic factors have only minor effects. Finally, our regression models explain ∼90% of variation in microsatellite mutability and can generate useful predictions for the studies of human diseases, forensics, and conservation genetics.[Supplemental material is available online at www.genome.org.]Microsatellites, i.e., tandemly recurring nucleotide sequences of short (1-6 bp) motifs, are ubiquitous in eukaryotic genomes and undergo rapid length changes due to insertion or deletion of one or multiple repeat units (Ellegren 2004;Pearson et al. 2005). Microsatellite mutation rates are high (10 ‫4מ‬-10 ‫2מ‬ mutations per locus per generation in humans) and vary greatly among loci (Ellegren 2004). The causes of this variation are not completely understood but are of great interest because microsatellite instability is implicated in cancer (Oda et al. 2005), expansions of microsatellites are responsible for over 40 neurological disorders (Pearson et al. 2005), and microsatellites are widely used markers in forensics and conservation genetics (Ellegren 2004). The most commonly proposed mutation mechanism for microsatellites is strand slippage, occurring predominantly during replication (Ellegren 2004); because of homology among microsatellite repeats, the two DNA strands might realign incorrectly after dissociation, introducing a loop at one strand and leading to microsatellite expansion/contraction (Ellegren 2004). However, experimental evidence indicates formation of unorthodox secondary DNA structures at microsatellites not only during replication but also during reco...

show abstract

The rise, fall and renaissance of microsatellites in eukaryotic genomes

2006

View full text Add to dashboard Cite

Microsatellites are among the most versatile of genetic markers, being used in an impressive number of biological applications. However, the evolutionary dynamics of these markers remain a source of contention. Almost 20 years after the discovery of these ubiquitous simple sequences, new genomic data are clarifying our understanding of the structure, distribution and variability of microsatellites in genomes, especially for the eukaryotes. While these new data provide a great deal of descriptive information about the nature and abundance of microsatellite sequences within eukaryotic genomes, there have been few attempts to synthesise this information to develop a global concept of evolution. This review provides an up-to-date account of the mutational processes, biases and constraints believed to be involved in the evolution of microsatellites, particularly with respect to the creation and degeneration of microsatellites, which we assert may be broadly viewed as a life cycle. In addition, we identify areas of contention that require further research and propose some possible directions for future investigation.

show abstract

Expansion of GAA triplet repeats in the human genome: unique origin of the FRDA mutation at the center of an Alu

Cited by 42 publications

References 27 publications

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

The genome-wide determinants of human and chimpanzee microsatellite evolution

The rise, fall and renaissance of microsatellites in eukaryotic genomes

Contact Info

Product

Resources

About