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CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex

Jennifer V. Gerbracht, View ORCID ProfileVolker Boehm, View ORCID ProfileThiago Britto-Borges, Sebastian Kallabis, Janica L. Wiederstein, Simona Ciriello, Dominik U. Aschemeier, View ORCID ProfileMarcus Krüger, View ORCID ProfileChristian K. Frese, Janine Altmüller, View ORCID ProfileChristoph Dieterich, View ORCID ProfileNiels H. Gehring
doi: https://doi.org/10.1101/811018
Jennifer V. Gerbracht
1Institute for Genetics, University of Cologne, 50674 Cologne, Germany
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Volker Boehm
1Institute for Genetics, University of Cologne, 50674 Cologne, Germany
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  • ORCID record for Volker Boehm
Thiago Britto-Borges
2Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, 69120 Heidelberg, Germany
3DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
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Sebastian Kallabis
4CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
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Janica L. Wiederstein
4CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
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Simona Ciriello
1Institute for Genetics, University of Cologne, 50674 Cologne, Germany
5AO Research Institute Davos, Clavadelerstrasse 8, CH-7270 Davos Platz, Switzerland
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Dominik U. Aschemeier
1Institute for Genetics, University of Cologne, 50674 Cologne, Germany
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Marcus Krüger
4CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
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  • ORCID record for Marcus Krüger
Christian K. Frese
4CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
6Max Planck Unit for the Science of Pathogens, 10117 Berlin, Germany
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Janine Altmüller
7Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
8Center for Molecular Medicine Cologne, University of Cologne, 50937 Cologne, Germany
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Christoph Dieterich
2Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, 69120 Heidelberg, Germany
3DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
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Niels H. Gehring
1Institute for Genetics, University of Cologne, 50674 Cologne, Germany
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  • ORCID record for Niels H. Gehring
  • For correspondence: ngehring@uni-koeln.de
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Abstract

The exon junction complex (EJC) is an essential constituent and regulator of spliced messenger ribonucleoprotein particles (mRNPs) in metazoans. As a core component of the EJC, CASC3 was described to be pivotal for EJC-dependent nuclear and cytoplasmic processes. However, recent evidence suggests that CASC3 functions differently from other EJC core proteins. Here, we have established human CASC3 knockout cell lines to elucidate the cellular role of CASC3. In the knockout cells, overall EJC composition and EJC-dependent splicing are unchanged. A transcriptome-wide analysis reveals that hundreds of mRNA isoforms targeted by nonsense-mediated decay (NMD) are upregulated. Mechanistically, recruiting CASC3 to reporter mRNAs by direct tethering or via binding to the EJC stimulates mRNA decay and endonucleolytic cleavage at the termination codon. Building on existing EJC-NMD models, we propose that CASC3 equips the EJC with the ability to communicate with the NMD machinery in the cytoplasm. Collectively, our results characterize CASC3 as a peripheral EJC protein that tailors the transcriptome by promoting the degradation of EJC-dependent NMD substrates.

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Posted January 11, 2020.
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CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex
Jennifer V. Gerbracht, Volker Boehm, Thiago Britto-Borges, Sebastian Kallabis, Janica L. Wiederstein, Simona Ciriello, Dominik U. Aschemeier, Marcus Krüger, Christian K. Frese, Janine Altmüller, Christoph Dieterich, Niels H. Gehring
bioRxiv 811018; doi: https://doi.org/10.1101/811018
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CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex
Jennifer V. Gerbracht, Volker Boehm, Thiago Britto-Borges, Sebastian Kallabis, Janica L. Wiederstein, Simona Ciriello, Dominik U. Aschemeier, Marcus Krüger, Christian K. Frese, Janine Altmüller, Christoph Dieterich, Niels H. Gehring
bioRxiv 811018; doi: https://doi.org/10.1101/811018

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