Specific inhibition of splicing factor activity by decoy RNA oligonucleotides.

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.

• Authors: Polina Denichenko, Maxim Mogilevsky, Antoine Cléry, Thomas Welte, Jakob Biran, Odelia Shimshon, Georgina D Barnabas, Miri Danan-Gotthold, Saran Kumar, Eylon Yavin, Erez Y Levanon, Frédéric H Allain, Tamar Geiger, Gil Levkowitz, Rotem Karni
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1590 (04 08 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30962446 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterogeneous-Nuclear Ribonucleoproteins
• Oligonucleotides
• PTBP1 protein, human
• RBFOX1 protein, human
• RNA Splicing Factors
• SRSF1 protein, human
• Polypyrimidine Tract-Binding Protein
• Serine-Arginine Splicing Factors

Topics

• Alternative Splicing
• Animals
• Animals, Genetically Modified
• Binding Sites
• Glioblastoma (genetics, pathology)
• HEK293 Cells
• Heterogeneous-Nuclear Ribonucleoproteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• MAP Kinase Signaling System (genetics)
• Muscle, Skeletal (growth & development)
• Nonsense Mediated mRNA Decay
• Oligonucleotides (chemistry, metabolism, pharmacology)
• Polypyrimidine Tract-Binding Protein (antagonists & inhibitors, genetics, metabolism)
• RNA Splicing Factors (antagonists & inhibitors, genetics, metabolism)
• Serine-Arginine Splicing Factors (antagonists & inhibitors, genetics, metabolism)
• Tandem Repeat Sequences
• Xenograft Model Antitumor Assays
• Zebrafish (embryology, genetics)