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Transposon clusters as substrates for aberrant splice-site activation

Transposon clusters as substrates for aberrant splice-site activation
Transposon clusters as substrates for aberrant splice-site activation
Transposed elements (TEs) have dramatically shaped evolution of the exon-intron structure and significantly contributed to morbidity, but how recent TE invasions into older TEs cooperate in generating new coding sequences is poorly understood. Employing an updated repository of new exon-intron boundaries induced by pathogenic mutations, termed DBASS, here we identify novel TE clusters that facilitated exon selection. To explore the extent to which such TE exons maintain RNA secondary structure of their progenitors, we carried out structural studies with a composite exon that was derived from a long terminal repeat (LTR78) and AluJ and was activated by a C>T mutation optimizing the 5’ splice site. Using a combination of SHAPE, DMS and enzymatic probing, we show that the disease-causing mutation disrupted a conserved AluJ stem that evolved from helix 3.3 (or 5b) of 7SL RNA, liberating a primordial GC 5’ splice site from the paired conformation for interactions with the spliceosome. The mutation also reduced flexibility of conserved residues in adjacent exon-derived loops of the central Alu hairpin, revealing a cross-talk between traditional and auxilliary splicing motifs that evolved from opposite termini of 7SL RNA and were approximated by Watson-Crick base-pairing already in organisms without spliceosomal introns. We also identify existing Alu exons activated by the same RNA rearrangement. Collectively, these results provide valuable TE exon models for studying formation and kinetics of pre-mRNA building blocks required for splice-site selection and will be useful for fine-tuning auxilliary splicing motifs and exon and intron size constraints that govern aberrant splice-site activation.
DBASS3, DBASS5, RNA processing, RNA secondary structure, Transposed element, genetic disease, lariat branch point, mutation, splice site
1547-6286
1-14
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e

Vorechovsky, Igor (2020) Transposon clusters as substrates for aberrant splice-site activation. RNA Biology, 1-14. (doi:10.1080/15476286.2020.1805909).

Record type: Article

Abstract

Transposed elements (TEs) have dramatically shaped evolution of the exon-intron structure and significantly contributed to morbidity, but how recent TE invasions into older TEs cooperate in generating new coding sequences is poorly understood. Employing an updated repository of new exon-intron boundaries induced by pathogenic mutations, termed DBASS, here we identify novel TE clusters that facilitated exon selection. To explore the extent to which such TE exons maintain RNA secondary structure of their progenitors, we carried out structural studies with a composite exon that was derived from a long terminal repeat (LTR78) and AluJ and was activated by a C>T mutation optimizing the 5’ splice site. Using a combination of SHAPE, DMS and enzymatic probing, we show that the disease-causing mutation disrupted a conserved AluJ stem that evolved from helix 3.3 (or 5b) of 7SL RNA, liberating a primordial GC 5’ splice site from the paired conformation for interactions with the spliceosome. The mutation also reduced flexibility of conserved residues in adjacent exon-derived loops of the central Alu hairpin, revealing a cross-talk between traditional and auxilliary splicing motifs that evolved from opposite termini of 7SL RNA and were approximated by Watson-Crick base-pairing already in organisms without spliceosomal introns. We also identify existing Alu exons activated by the same RNA rearrangement. Collectively, these results provide valuable TE exon models for studying formation and kinetics of pre-mRNA building blocks required for splice-site selection and will be useful for fine-tuning auxilliary splicing motifs and exon and intron size constraints that govern aberrant splice-site activation.

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2020 RNA Biol by Alvarez et al - Accepted Manuscript
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2020 RNA Biol - Transposon clusters as substrates for aberrant splice site activation - Version of Record
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More information

Accepted/In Press date: 1 August 2020
e-pub ahead of print date: 23 September 2020
Keywords: DBASS3, DBASS5, RNA processing, RNA secondary structure, Transposed element, genetic disease, lariat branch point, mutation, splice site

Identifiers

Local EPrints ID: 444241
URI: http://eprints.soton.ac.uk/id/eprint/444241
ISSN: 1547-6286
PURE UUID: ad3f1ea3-4d3f-4479-bbaa-2c975e7f9d92

Catalogue record

Date deposited: 02 Oct 2020 16:31
Last modified: 26 Nov 2021 05:57

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