The regulation properties of RNA secondary structure in alternative splicing

Bartyś, Natalia; Kierzek, Ryszard; Lisowiec-Wąchnicka, Jolanta

doi:10.1016/j.bbagrm.2019.07.002

Cited by 28 publications

(21 citation statements)

References 124 publications

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“…While PE inclusion was completely reverted in most of the cases by at least one of the designed AONs, 100% splicing correction could not be achieved for variant c.3050+370C>T. As already commented, the targeting of the 205-nt PE gave rise to the inclusion of a shorter PE, which was increased by the treatment with AON1 due to its binding to SC35 motifs only present in the larger PE. Considering that splicing is a dynamic and complex process [ 42 , 45 , 46 , 47 ], it is very difficult to predict alternative events that might be activated due to the use of splicing modulation molecules. In addition, splicing has been described as a non-sequential process by in silico real-time visualization approaches [ 48 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

Tomkiewicz

Suárez-Herrera

Cremers

et al. 2021

IJMS

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The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes ABCA4 a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In this study, AON-based splicing modulation was assessed for 15 recently described intronic variants (three near-exon and 12 deep-intronic variants). In total, 26 AONs were designed and tested in vitro using a midigene-based splice system. Overall, partial or complete splicing correction was observed for two variants causing exon elongation and all variants causing pseudoexon inclusion. Together, our results confirm the high potential of AONs for the development of future RNA therapies to correct splicing defects causing STGD1.

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Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

Tomkiewicz

Suárez-Herrera

Cremers

et al. 2021

IJMS

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“…It is also possible that Anti-N1 could trigger structural rearrangements in pre-mRNA. The role of an RNA structure in pre-mRNA splicing regulation is a growing area of interest [40,[108][109][110][111], and an ASO-based approach has been employed to abrogate structural elements critical for splicing control [39,112]. Off-target sites of Anti-N1 are expected to be randomly distributed throughout pre-mRNAs with their high prevalence in introns due to their (introns') large size.…”

Section: Discussionmentioning

confidence: 99%

High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome

Ottesen

Luo

Singh

et al. 2021

IJMS

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Intronic splicing silencer N1 (ISS-N1) located within Survival Motor Neuron 2 (SMN2) intron 7 is the target of a therapeutic antisense oligonucleotide (ASO), nusinersen (Spinraza), which is currently being used for the treatment of spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. The discovery of ISS-N1 as a promising therapeutic target was enabled in part by Anti-N1, a 20-mer ASO that restored SMN2 exon 7 inclusion by annealing to ISS-N1. Here, we analyzed the transcriptome of SMA patient cells treated with 100 nM of Anti-N1 for 30 h. Such concentrations are routinely used to demonstrate the efficacy of an ASO. While 100 nM of Anti-N1 substantially stimulated SMN2 exon 7 inclusion, it also caused massive perturbations in the transcriptome and triggered widespread aberrant splicing, affecting expression of essential genes associated with multiple cellular processes such as transcription, splicing, translation, cell signaling, cell cycle, macromolecular trafficking, cytoskeletal dynamics, and innate immunity. We validated our findings with quantitative and semiquantitative PCR of 39 candidate genes associated with diverse pathways. We also showed a substantial reduction in off-target effects with shorter ISS-N1-targeting ASOs. Our findings are significant for implementing better ASO design and dosing regimens of ASO-based drugs.

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“…The secondary structure of the pre-mRNA substrate can also affect (alternative) splicing (reviewed in [ 140 ]). For example, stem-loop hairpin structures caused by intramolecular basepairing alter the local accessibility for trans-acting proteins.…”

Section: Structure and Function Of The (Supra) Spliceosomementioning

confidence: 99%

Biology of the mRNA Splicing Machinery and Its Dysregulation in Cancer Providing Therapeutic Opportunities

Blijlevens

Beusechem

2021

IJMS

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Dysregulation of messenger RNA (mRNA) processing—in particular mRNA splicing—is a hallmark of cancer. Compared to normal cells, cancer cells frequently present aberrant mRNA splicing, which promotes cancer progression and treatment resistance. This hallmark provides opportunities for developing new targeted cancer treatments. Splicing of precursor mRNA into mature mRNA is executed by a dynamic complex of proteins and small RNAs called the spliceosome. Spliceosomes are part of the supraspliceosome, a macromolecular structure where all co-transcriptional mRNA processing activities in the cell nucleus are coordinated. Here we review the biology of the mRNA splicing machinery in the context of other mRNA processing activities in the supraspliceosome and present current knowledge of its dysregulation in lung cancer. In addition, we review investigations to discover therapeutic targets in the spliceosome and give an overview of inhibitors and modulators of the mRNA splicing process identified so far. Together, this provides insight into the value of targeting the spliceosome as a possible new treatment for lung cancer.

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The regulation properties of RNA secondary structure in alternative splicing

Cited by 28 publications

References 124 publications

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome

Biology of the mRNA Splicing Machinery and Its Dysregulation in Cancer Providing Therapeutic Opportunities

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