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

doi:10.1038/s41467-019-09523-0

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

Human Molecular Genetics Biochemistry

Research output: Contribution to journal › Article › peer-review

69 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 language	English
Article number	1590
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09523-0
State	Published - 1 Dec 2019

Funding

Funders	Funder number
Alex U. Soyka Pancreatic Cancer Research Project
Israel Innovation Authority
KAMIN
Israel Science Foundation	1290/12

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-09523-0

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Denichenko, P., Mogilevsky, M., Cléry, A., Welte, T., Biran, J., Shimshon, O., Barnabas, G. D., Danan-Gotthold, M., Kumar, S., Yavin, E., Levanon, E. Y., Allain, F. H., Geiger, T., Levkowitz, G., & Karni, R. (2019). Specific inhibition of splicing factor activity by decoy RNA oligonucleotides. Nature Communications, 10(1), Article 1590. https://doi.org/10.1038/s41467-019-09523-0

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AU - Denichenko, Polina

AU - Mogilevsky, Maxim

AU - Cléry, Antoine

AU - Welte, Thomas

AU - Biran, Jakob

AU - Shimshon, Odelia

AU - Barnabas, Georgina D.

AU - Danan-Gotthold, Miri

AU - Kumar, Saran

AU - Yavin, Eylon

AU - Levanon, Erez Y.

AU - Allain, Frédéric H.

AU - Geiger, Tamar

AU - Levkowitz, Gil

AU - Karni, Rotem

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AB - 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.

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Specific inhibition of splicing factor activity by decoy RNA oligonucleotides

Abstract

Funding

UN SDGs

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