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Mol Cell. 2018 Nov 1;72(3):482-495.e7. doi: 10.1016/j.molcel.2018.08.030.

Exon Junction Complexes Suppress Spurious Splice Sites to Safeguard Transcriptome Integrity.

Author information

1
Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
2
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
3
Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
4
Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, 781039-Guwahati, Assam, India.
5
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
6
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50937 Cologne, Germany.
7
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany. Electronic address: christoph.dieterich@uni-heidelberg.de.
8
Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Electronic address: ngehring@uni-koeln.de.

Abstract

Productive splicing of human precursor messenger RNAs (pre-mRNAs) requires the correct selection of authentic splice sites (SS) from the large pool of potential SS. Although SS consensus sequence and splicing regulatory proteins are known to influence SS usage, the mechanisms ensuring the effective suppression of cryptic SS are insufficiently explored. Here, we find that many aberrant exonic SS are efficiently silenced by the exon junction complex (EJC), a multi-protein complex that is deposited on spliced mRNA near the exon-exon junction. Upon depletion of EJC proteins, cryptic SS are de-repressed, leading to the mis-splicing of a broad set of mRNAs. Mechanistically, the EJC-mediated recruitment of the splicing regulator RNPS1 inhibits cryptic 5'SS usage, while the deposition of the EJC core directly masks reconstituted 3'SS, thereby precluding transcript disintegration. Thus, the EJC protects the transcriptome of mammalian cells from inadvertent loss of exonic sequences and safeguards the expression of intact, full-length mRNAs.

KEYWORDS:

EJC; alternative splicing; cryptic splice sites; exon junction complex; gene expression; mRNA processing

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