Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting

Bergquist, Helen; Rocha, Cristina S. J.; Álvarez-Asencio, Rubén; Nguyen, Chi-Hung; Rutland, Mark W.; Smith, C. I. Edvard; Good, Liam; Nielsen, Peter E.; Zain, Rula

doi:10.1371/journal.pone.0165788

Cited by 18 publications

(33 citation statements)

References 70 publications

(79 reference statements)

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“…However, the lasting effectiveness of this therapy may still be limited by ongoing somatic expansions. Perhaps this therapy will prove effective in combination with treatments designed to disrupt secondary structures[129], slow somatic expansions [81] or promote somatic contractions [130,131].…”

Section: Transcription and Fragility In Frda And Fxs: Consequences Anmentioning

confidence: 99%

Cis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics

McGinty

Mirkin

2018

Trends in Genetics

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Over 30 hereditary diseases are caused by the expansion of microsatellite repeats. The length of the expandable repeat is the main hereditary determinant of these disorders. They are also affected by numerous genomic variants that are either nearby (cis) or physically separated from (trans) the repetitive locus, which we review here. These genetic variants have largely been elucidated in model systems using gene knockouts, while a few have been directly observed as single-nucleotide polymorphisms (SNPs) in patients. There is a notable disconnect between these two bodies of knowledge: knockouts poorly approximate the SNP-level variation in human populations that gives rise to medically relevant cis- and trans-modifiers, while the rarity of these diseases limits the statistical power of SNP-based analysis in humans. We propose that high-throughput SNP-based screening in model systems could become a useful approach to quickly identify and characterize modifiers of clinical relevance for patients.

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Section: Transcription and Fragility In Frda And Fxs: Consequences Anmentioning

confidence: 99%

Cis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics

McGinty

Mirkin

2018

Trends in Genetics

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“…Furthermore, we found that sequence-specific binding using repeat-specific PNA oligomers resulted in complete disruption of the triplex formed and LNA ONs showed similar results (Fig. 5 ) [ 42 ]. These findings are currently employed in FRDA patient cell lines to upregulate FXN transcription and increase the levels of mRNA and protein (manuscript in preparation).…”

Section: Oligonucleotide Targeting Of Non-b-dna Structuresmentioning

confidence: 82%

“…Furthermore, PNA binds to dsDNA and forms double- and triple-strand structures (Fig. 3 ) through Watson-Crick, Hoogsteen, or reverse-Hoogsteen base pairing [ 42 ]. PNA [ 43 ] and LNA [ 44 , 45 ] can invade dsDNA and form different PNA:DNA, and LNA:DNA, complexes, respectively (Fig.…”

Section: Chemical Modifications Of Oligonucleotidesmentioning

confidence: 99%

Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

Zain

Smith

2019

Neurotherapeutics

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Nucleotide repeat disorders encompass more than 30 diseases, most of which show dominant inheritance, such as Huntington's disease, spinocerebellar ataxias, and myotonic dystrophies. Yet others, including Friedreich's ataxia, are recessively inherited. A common feature is the presence of a DNA tandem repeat in the disease-associated gene and the propensity of the repeats to expand in germ and in somatic cells, with ensuing neurological and frequently also neuromuscular defects. Repeat expansion is the most frequent event in these diseases; however, sequence contractions, deletions, and mutations have also been reported. Nucleotide repeat sequences are predisposed to adopt non-B-DNA conformations, such as hairpins, cruciform, and intramolecular triple-helix structures (triplexes), also known as H-DNA. For gain-of-function disorders, oligonucleotides can be used to target either transcripts or duplex DNA and in diseases with recessive inheritance oligonucleotides may be used to alter repressive DNA or RNA conformations. Most current treatment strategies are aimed at altering transcript levels, but therapies directed against DNA are also emerging, and novel strategies targeting DNA, instead of RNA, are described. Different mechanisms using modified oligonucleotides are discussed along with the structural aspects of repeat sequences, which can influence binding modes and efficiencies.Key Words Chromatin . DNA repair . fragile X syndrome . locked nucleic acid . spinal and bulbar muscular atrophy . non-canonical DNA structure Neurotherapeutics (2019) 16:248-262 https://doi.

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“…Reports have shown that PNA can both prevent and induce the formation of G-quadruplexes [ 47 ]. Bergquist et al, have demonstrated that PNA and LNA ONs can, by strand-invasion, disrupt H-DNA structures within expanded triplet-repeats, present in various diseases, such as in Friedreich’s ataxia [ 48 ]. To increase the stability of PNA- or LNA-based DNA complexes, clamp type strand-invading ONs have been developed, so called bisPNA and bisLNA, respectively.…”

Section: Introductionmentioning

confidence: 99%

Oligonucleotide Binding to Non-B-DNA in MYC

et al. 2019

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MYC, originally named c-myc, is an oncogene deregulated in many different forms of cancer. Translocation of the MYC gene to an immunoglobulin gene leads to an overexpression and the development of Burkitt’s lymphoma (BL) [1]. Sporadic BL constitutes one subgroup where one of the translocation sites is located at the 5′-vicinity of the two major MYC promoters P1 and P2. A non-B-DNA forming sequence within this region has been reported with the ability to form an intramolecular triplex (H-DNA) or a G-quadruplex[2,3]. We have examined triplex formation at this site first by using a 17 bp triplex-forming oligonucleotide (TFO) and a double strand DNA (dsDNA) target corresponding to the MYC sequence. An antiparallel purine-motif triplex was detected using electrophoretic mobility shift assay. Furthermore, we probed for H-DNA formation using the BQQ-OP based triplex-specific cleavage assay, which indicated the formation of the structure in the supercoiled plasmid containing the corresponding region of the MYC promoter. Targeting non-B-DNA structures has therapeutic potential; therefore, we investigated their influence on strand-invasion of anti-gene oligonucleotides (ON)s. We show that in vitro, non-B-DNA formation at the vicinity of the ON target site facilitates dsDNA strand-invasion of the anti-gene ONs.

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Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting

Cited by 18 publications

References 70 publications

Cis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics

Cis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics

Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

Oligonucleotide Binding to Non-B-DNA in MYC

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