Deciphering human nonsense-mediated mRNA decay (NMD)
Christoph Dieterich
Klaus Tschira Institute for Computational Cardiology
Heidelberg University Hospital
E-mail: christoph.dieterich(at)uni-heidelberg.de
For more information and contact visit the Dieterich website
Niels Gehring
Institute for Genetics
University of Cologne
E-mail: ngehring(at)uni-koeln.de
For more information and contact visit the Gehring lab.
Abstract
In eukaryotic cells several quality control mechanisms help to detect defective or irregular mRNAs and to avoid the production of incorrect polypeptides. A well-studied degradation pathway, referred to as nonsense mediated mRNA decay (NMD), degrades transcripts containing premature translation termination codons (PTC). NMD exists in all eukaryotic organisms and employs a conserved set of core factors to eliminate aberrant transcripts that fail to terminate translation at a proper position.
The activity of NMD is not restricted to mRNAs carrying disease-causing nonsense mutations. In fact, the majority of NMD substrates is produced by alternative mRNA processing, resulting in the inclusion of PTCs into the mature transcript. Hence, NMD functions as a general modulator of gene expression and directly or indirectly alters the expression levels of a substantial part of the transcriptome in eukaryotic cells.
The activity of NMD is not restricted to mRNAs carrying disease-causing nonsense mutations. In fact, the majority of NMD substrates is produced by alternative mRNA processing, resulting in the inclusion of PTCs into the mature transcript. Hence, NMD functions as a general modulator of gene expression and directly or indirectly alters the expression levels of a substantial part of the transcriptome in eukaryotic cells.
Project-related publications
Boehm V, Kueckelmann S, Gerbracht JV, Britto-Borges T, Altmüller J, Dieterich C, Gehring NH.
Nonsense-mediated mRNA decay relies on “two-factor authentication” by SMG5-SMG7bioRxiv 2020.07.07.191437; doi: https://doi.org/10.1101/2020.07.07.191437
Gerbracht JV, Boehm V, Britto-Borges T, Kallabis S, Wiederstein JL, Ciriello S, Aschemeier DU, Krüger M, Frese CK, Altmüller J, Dieterich C, Gehring NH
CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex. Nucleic Acids Res. 2020 Sep 4;48(15):8626-8644 doi: 10.1093/nar/gkaa564.
Boehm V, Britto-Borges T, Steckelberg AL, Singh KK, Gerbracht JV, Gueney E, Blazquez L, Altmüller J, Dieterich C, Gehring NH.
Exon Junction Complexes Suppress Spurious Splice Sites to Safeguard Transcriptome Integrity. Mol Cell. 2018 Nov 1;72(3):482-495.e7. doi: 10.1016/j.molcel.2018.08.030.