Deciphering human nonsense-mediated mRNA decay (NMD)

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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 about 5% of the transcriptome in eukaryotic cells. Despite the importance of NMD for the composition of the transcriptome, only a small number of transcripts that activate NMD by alternative processing have been studied in detail. In order to close this knowledge gap, we will use state-of-the-art methods to manipulate the NMD machinery, which will allow us to compile a catalogue of all NMD-activating transcript isoforms in human cells. Using this new set of NMD targets we will address important mechanistic questions regarding the early commitment phase as well as the degradation phase of NMD. We will also produce computational methods to systematically test the effect of NMD on post-transcriptional regulation of gene expression.