hnRNP A1 induces aberrant CFTR exon 9 splicing via a newly discovered ESS element

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F25%3A00141394" target="_blank" >RIV/00216224:14740/25:00141394 - isvavai.cz</a>
Result on the web
<a href="https://www.life-science-alliance.org/content/8/9/e202402720" target="_blank" >https://www.life-science-alliance.org/content/8/9/e202402720</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.26508/lsa.202402720" target="_blank" >10.26508/lsa.202402720</a>

Result language
angličtina
Original language name
hnRNP A1 induces aberrant CFTR exon 9 splicing via a newly discovered ESS element
Original language description
RNA-protein interactions play a key role in the aberrant splicing of CFTR exon 9. Exon 9 skipping leads to the production of a nonfunctional chloride channel associated with severe forms of cystic fibrosis. The missplicing depends on TDP-43 binding to an extended UG-rich binding site upstream of CFTR exon 9 3′ splicing site (3′ss) and is associated with concomitant hnRNP A1 recruitment. Although TDP-43 is the dominant inhibitor of exon 9 inclusion, the role of hnRNP A1, a protein with two RNA recognition motifs, remained unclear. In this work, we have studied the interaction between hnRNP A1 and the CFTR pre-mRNA using NMR spectroscopy and Isothermal Titration Calorimetry. The affinities are submicromolar, and Isothermal Titration Calorimetry data suggest complexes with a 1:1 stoichiometry. NMR titrations reveal that hnRNP A1 interacts with model CTFR 3′ss sequences in a fast exchange regime at the NMR timescale. Splicing assays finally show that this hnRNP A1 binding site represents a previously unknown exonic splicing silencer element. Together, our results shed light on the mechanism of aberrant CFTR exon 9 splicing.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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