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BAY61-3606 Alters snRNP Composition and Enhances Usage of Suboptimal Splice Acceptor Site

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Title: BAY61-3606 Alters snRNP Composition and Enhances Usage of Suboptimal Splice Acceptor Site
Authors: Tomita, Kenji Browse this author
Nakagawa, Shinichi Browse this author →KAKEN DB
Ariga, Hiroyoshi Browse this author →KAKEN DB
Maita, Hiroshi Browse this author →KAKEN DB
Keywords: splicing
split luciferase
small nuclear ribonucleoprotein
fidelity
small compound screening
Issue Date: 1-Feb-2023
Publisher: The Pharmaceutical Society of Japan
Journal Title: Biological & pharmaceutical bulletin
Volume: 46
Issue: 2
Start Page: 147
End Page: 157
Publisher DOI: 10.1248/bpb.b22-00471
Abstract: Intron recognition by the spliceosome mainly depends on conserved intronic sequences such as 5' splice sites, 3' splice sites, and branch sites. Therefore, even substitution of just a single nucleotide in a 5' or 3' splice site abolishes the splicing at the mutated site and leads to cryptic splice site usage. A number of disease -causative mutations have been found in 5' and 3' splice sites, but the genes with these mutations still maintain the correct protein-coding sequence, so recovery of splicing at the mutated splice site may produce a normal protein. Mutations in the spliceosome components have been shown to change the balance between the confor-mational transition and disassembly of the spliceosome, which affects the decision about whether the reaction of the incorporated substrate will proceed. In addition, the lower disassembly rate caused by such mutations induces splicing of the mutated splice site. We hypothesized that small compounds targeting the spliceosome may include a compound mimicking the effect of those mutations. Thus, we screened a small-compound li-brary and identified a compound, BAY61-3606, that changed the cellular small nuclear ribonucleoprotein composition and also showed activity of enhancing splicing at the mutated 3' splice site of the reporter gene, as well as splicing at the suboptimal 3' splice site of endogenous cassette exons. These results indicate that further analysis of the mechanism of action of BAY61-3606 could enable modulation of the fidelity of splicing.
Type: article
URI: http://hdl.handle.net/2115/88940
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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