Specific inhibition of splicing factor activity by decoy RNA oligonucleotides

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.

Original languageAmerican English
Article number1590
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

Bibliographical note

Funding Information:
The authors wish to thank Dr. Zahava Kluger for comments on the manuscript and members of the Karni lab for helpful discussions. This work was supported by the Israel Science Foundation (ISF Grants no' 1290/12 to R.K.), Alex U. Soyka Pancreatic Cancer Research Project (to R.K.) and KAMIN (Israel Innovation Authority) grant (to R.K.). We thank the SNF-NCCR RNA and Disease for financial support to F.H.T.A and A.C.

Publisher Copyright:
© 2019, The Author(s).

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