An antisense microwalk reveals critical role of an intronic position linked to a unique long-distance interaction in pre-mRNA splicing

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dc.contributor.author Singh, Natalia
dc.contributor.author Hollinger, Katrin
dc.contributor.author Singh, Ravindra
dc.contributor.author Bhattacharya, Dhruva
dc.contributor.author Singh, Ravindra
dc.contributor.department Biomedical Sciences
dc.contributor.department Genetics
dc.date 2018-02-17T11:21:49.000
dc.date.accessioned 2020-06-30T00:53:07Z
dc.date.available 2020-06-30T00:53:07Z
dc.date.copyright Fri Jan 01 00:00:00 UTC 2010
dc.date.issued 2010-01-01
dc.description.abstract <p>Here we report a novel finding of an antisense oligonucleotide (ASO) microwalk in which we examined the position-specific role of intronic residues downstream from the 5′ splice site (5′ ss) of <em>SMN2</em> exon 7, skipping of which is associated with spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Our results revealed the inhibitory role of a cytosine residue at the 10th intronic position (<sup>10</sup>C), which is neither conserved nor associated with any known splicing motif. Significance of <sup>10</sup>C emerged from the splicing pattern of <em>SMN2</em> exon 7 in presence of a 14-mer ASO (L14) that sequestered two adjacent hnRNP A1 motifs downstream from <sup>10</sup>C and yet promoted <em>SMN2</em> exon 7 skipping. Another 14-mer ASO (F14) that sequestered both, <sup>10</sup>C and adjacent hnRNP A1 motifs, led to a strong stimulation of <em>SMN2</em> exon 7 inclusion. The inhibitory role of <sup>10</sup>C was found to be tightly linked to its unpaired status and specific positioning immediately upstream of a RNA:RNA helix formed between the targeting ASO and its intronic target. Employing a heterologous context as well as changed contexts of <em>SMN2</em> intron 7, we show that the inhibitory effect of unpaired <sup>10</sup>C is dependent upon a long-distance interaction involving downstream intronic sequences. Our report furnishes one of the rare examples in which an ASO-based approach could be applied to unravel the critical role of an intronic position that may not belong to a linear motif and yet play significant role through long-distance interactions.</p>
dc.description.comments <p>This is an article from <em>RNA</em> 16 (2010): 1167, doi:<a href="http://dx.doi.org/10.1261/rna.2154310" target="_blank">10.1261/rna.2154310</a>. Posted with permission.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/bms_pubs/2/
dc.identifier.articleid 1005
dc.identifier.contextkey 8051565
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath bms_pubs/2
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/11142
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/bms_pubs/2/2010_Singh_AntisenseMicrowalk.pdf|||Fri Jan 14 22:05:48 UTC 2022
dc.source.uri 10.1261/rna.2154310
dc.subject.disciplines Medical Biochemistry
dc.subject.disciplines Medical Genetics
dc.subject.disciplines Other Medical Sciences
dc.subject.keywords SMN
dc.subject.keywords alternative splicing
dc.subject.keywords intron 7
dc.subject.keywords exon 7
dc.subject.keywords ISS-N1
dc.subject.keywords GC-rich
dc.subject.keywords antisense oligonucleotide
dc.subject.keywords ASO
dc.subject.keywords SMA
dc.title An antisense microwalk reveals critical role of an intronic position linked to a unique long-distance interaction in pre-mRNA splicing
dc.type article
dc.type.genre article
dspace.entity.type Publication
relation.isAuthorOfPublication d5765265-0e5d-4de9-8e17-19842ab75544
relation.isOrgUnitOfPublication 184db3f2-d93f-4571-8ad7-07c8a9e6a5c9
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