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Nat Commun. 2019 Apr 8;10(1):1590. doi: 10.1038/s41467-019-09523-0.

Specific inhibition of splicing factor activity by decoy RNA oligonucleotides.

Author information

1
Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, 9112001, Israel.
2
Institute of Molecular Biology and Biophysics, ETH Zurich, Hönggerbergring 64, 8093, Zurich, Switzerland.
3
Dynamic Biosensors, GmbH, Lochhamer Strasse 15, 82152, Martinsried/Planegg, Germany.
4
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
5
Department of Medicinal Chemistry, Institute for Drug Research, Hebrew University-Hadassah Medical School, Jerusalem, 9112001, Israel.
6
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel.
7
Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 52900, Israel.
8
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University-Hadassah Medical School, Jerusalem, 9112001, Israel.
9
Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, 9112001, Israel. rotemka@ekmd.huji.ac.il.

Abstract

Alternative splicing, a fundamental step in gene expression, is deregulated in many diseases. Splicing factors (SFs), which regulate this process, are up- or down regulated or mutated in several diseases including cancer. To date, there are no inhibitors that directly inhibit the activity of SFs. We designed decoy oligonucleotides, composed of several repeats of a RNA motif, which is recognized by a single SF. Here we show that decoy oligonucleotides targeting splicing factors RBFOX1/2, SRSF1 and PTBP1, can specifically bind to their respective SFs and inhibit their splicing and biological activities both in vitro and in vivo. These decoy oligonucleotides present an approach to specifically downregulate SF activity in conditions where SFs are either up-regulated or hyperactive.

PMID:
30962446
PMCID:
PMC6453957
DOI:
10.1038/s41467-019-09523-0
[Indexed for MEDLINE]
Free PMC Article

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