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Retinitis pigmentosa-linked mutation in DHX38 modulates its splicing activity
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SYSNO ASEP 0558860 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Retinitis pigmentosa-linked mutation in DHX38 modulates its splicing activity Author(s) Obuca, Mina (UMG-J)
Cvačková, Zuzana (UMG-J) RID
Kubovčiak, Jan (UMG-J)
Kolář, Michal (UMG-J) RID, ORCID
Staněk, David (UMG-J) RIDNumber of authors 5 Article number e0265742 Source Title PLoS ONE. - : Public Library of Science - ISSN 1932-6203
Roč. 17, č. 4 (2022)Number of pages 14 s. Publication form Online - E Language eng - English Country US - United States Keywords pre-messenger-rna ; atpase prp16 ; helix i ; spliceosome ; mechanism ; fidelity ; impairs ; gene Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology R&D Projects GC18-01911J GA ČR - Czech Science Foundation (CSF) EF16_019/0000785 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000804836900087 DOI 10.1371/journal.pone.0265742 Annotation Retinitis pigmentosa (RP) is a hereditary disease affecting tens of thousands of people world-wide. Here we analyzed the effect of an amino acid substitution in the RNA helicase DHX38 (Prp16) causing RP. DHX38 has been proposed as the helicase important for the 2(nd) step of splicing. We showed that DHX38 associates with key splicing factors involved in both splicing steps but did not find any evidence that the RP mutations changes DHX38 interaction profile with the spliceosome. We further downregulated DHX38 and monitored changes in splicing. We observed only minor perturbations of general splicing but detected modulation of ~70 alternative splicing events. Next, we probed DHX38 function in splicing of retina specific genes and found that FSCN2 splicing is dependent on DHX38. In addition, RHO splicing was inhibited specifically by expression of DHX38 RP variant. Finally, we showed that overexpression of DHX38 promotes usage of canonical as well as cryptic 5' splice sites in HBB splicing reporter. Together, our data show that DHX38 is a splicing factor that promotes splicing of cryptic splice sites and regulate alternative splicing. We further provide evidence that the RP-linked substitution G332D modulates DHX38 splicing activity. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265742
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