Anti-sense DNA d(GGCCCC)n expansions in C9ORF72 form i-motifs and protonated hairpins

Kovanda, Anja; Zalar, Matja; Šket, Primož; Plavec, Janez; Rogelj, Boris

doi:10.1038/srep17944

Cited by 76 publications

(76 citation statements)

References 34 publications

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ The precise information about the structure of the hairpin-like structure is not yet known. However, it has been reported that a hairpin-like structure can form from the C-rich strand of C9ORF72 consisting of a C 4 G 2 repeat 44 . This hairpin structure is formed with Watson-Crick base pairing of the cytosine and guanine bases, and may further fold into a tertiary structure.…”

Section: Discussionmentioning

confidence: 99%

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Takahashi

Bhattacharjee

Ghosh

et al. 2020

Sci Rep

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The relationship of i-motif DNAs with cancer has prompted the development of specific ligands to detect and regulate their formation. Some plant flavonols show unique fluorescence and anti-cancer properties, which suggest the utility of the theranostics approach to cancer therapy related to i-motif DNA. We investigated the effect of the plant flavonol, fisetin (Fis), on the physicochemical property of i-motif DNAs. Binding of Fis to the i-motif from the promoter region of the human vascular endothelial growth factor (VEGF) gene dramatically induced the excited state intramolecular proton transfer (ESIPT) reaction that significantly enhanced the intensity of the tautomer emission band of Fis. This unique response was due to the coincidence of the structural change from i-motif to the hairpin-like structure which is stabilized via putative Watson-Crick base pairs between some guanines within the loop region of the i-motif and cytosines in the structure. As a result, the VEGF i-motif did not act as a replication block in the presence of fis, which indicates the applicability of fis for the regulation of gene expression of VEGF. The fluorescence and biological properties of Fis may be utilised for theranostics applications for cancers related to a specific cancer-related gene, such as VEGF. Besides the canonical right-handed DNA double helix, DNA sequences can adopt non-canonical structures, including G-quadruplexes (G4s) and i-motifs, that are stabilised by non-Watson-Crick base pairing 1. G4 structures are formed from guanine (G)-rich sequences, whereas i-motifs are formed from the cytosine (C)-rich sequences. The i-motif structure consists of two parallel duplexes that intercalate with each other in an antiparallel orientation (Fig. 1A). The parallel duplexes are held together via hydrogen bonding between a neutral cytosine (C) and a protonated cytosine (C +) (Fig. 1B) 2. The formation of an i-motif structure occurs more readily in an acidic condition because protonation of cytosine is required to form a hemiprotonated CC + base pair. However, there is increasing evidence to suggest that the i-motif structures can also form at neutral pH 3,4 and even in the nuclei of living mammalian cells 5,6. The i-motif forming sequences are found in or near the promoter regions of >40% of all human genes, which can regulate the expressions of genes like Bcl2 7,8 and HRAS 9. Furthermore, the i-motif along the cancer-related DNA sequences strongly inhibits DNA replication 10. Therefore, i-motif DNAs are attractive targets for the diagnosis of cancer risk and to treat cancer by the modulation of gene transcription and replication. Considering the use of specific targeted therapy based on specific targeted test (i.e., theranostics) for both diagnosis and therapeutics, some ligands that both emit a fluorescent signal upon binding to a specific i-motif and regulate the transcription or replication of the target gene are required. Currently, no ligands have such dual functions for i-motif DNAs. Flavonols and other related compounds o...

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Section: Discussionmentioning

confidence: 99%

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Takahashi

Bhattacharjee

Ghosh

et al. 2020

Sci Rep

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“…Whereas C9ORF72-S can form G-quadruplexes [46,55,116] that are known to regulate transcription and gene expression [150], the C-rich C9ORF72-AS repeats may not form similar structures. Instead, the G 2 C 4 expansions in C9ORF72-AS may form a C-rich motif [65] that likely affects genome stability and transcription [1]. Notably, an A-form-like double-helix with a tandem C:C mismatch has been observed in a crystal structure of the C9ORF72-AS repeat expansion, suggesting that different structural forms of C9ORF72-AS might regulate disease progression [38].…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

Chen

2020

J Biomed Sci

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Long non-coding RNAs (lncRNAs) have gained increasing attention as they exhibit highly tissue-and cell-type specific expression patterns. LncRNAs are highly expressed in the central nervous system and their roles in the brain have been studied intensively in recent years, but their roles in the spinal motor neurons (MNs) are largely unexplored. Spinal MN development is controlled by precise expression of a gene regulatory network mediated spatiotemporally by transcription factors, representing an elegant paradigm for deciphering the roles of lncRNAs during development. Moreover, many MN-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are associated with RNA metabolism, yet the link between MN-related diseases and lncRNAs remains obscure. In this review, we summarize lncRNAs known to be involved in MN development and disease, and discuss their potential future therapeutic applications.

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“…The intronic (G 4 C 2 ) hexanucleotide repeat expansion within the C9ORF72 gene has been shown to be the main genetic feature of ALS 14 – 16 . As well as giving rise to exotic DNA features such as G-quadruplexes and i-motifs 17 , 18 , the expanded repeats undergo both aberrant and unconventional processing (reviewed in Vatovec et al . 19 ), which further supports disease-associated changes in RNA metabolism as a core mechanism in ALS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of microRNAs and other small RNAs in muscle tissue of patients with ALS and healthy age-matched controls

Kovanda

Leonardis

Zidar

et al. 2018

Sci Rep

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Amyotrophic lateral sclerosis is a late-onset disorder primarily affecting motor neurons and leading to progressive and lethal skeletal muscle atrophy. Small RNAs, including microRNAs (miRNAs), can serve as important regulators of gene expression and can act both globally and in a tissue-/cell-type-specific manner. In muscle, miRNAs called myomiRs govern important processes and are deregulated in various disorders. Several myomiRs have shown promise for therapeutic use in cellular and animal models of ALS; however, the exact miRNA species differentially expressed in muscle tissue of ALS patients remain unknown. Following small RNA-Seq, we compared the expression of small RNAs in muscle tissue of ALS patients and healthy age-matched controls. The identified snoRNAs, mtRNAs and other small RNAs provide possible molecular links between insulin signaling and ALS. Furthermore, the identified miRNAs are predicted to target proteins that are involved in both normal processes and various muscle disorders and indicate muscle tissue is undergoing active reinnervation/compensatory attempts thus providing targets for further research and therapy development in ALS.

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Anti-sense DNA d(GGCCCC)n expansions in C9ORF72 form i-motifs and protonated hairpins

Cited by 76 publications

References 34 publications

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

Differential expression of microRNAs and other small RNAs in muscle tissue of patients with ALS and healthy age-matched controls

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