Single-Molecule Imaging Uncovers Rules Governing Nonsense-Mediated mRNA Decay

Tim A Hoek, Deepak Khuperkar, Rik G H Lindeboom, Stijn Sonneveld, Bram M P Verhagen, Sanne Boersma, Michiel Vermeulen, Marvin E Tanenbaum

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

Nonsense-mediated decay (NMD) is a surveillance system that degrades mRNAs containing a premature termination codon (PTC) and plays important roles in protein homeostasis and disease. The efficiency of NMD is variable, impacting the clinical outcome of genetic mutations. However, limited resolution of bulk analyses has hampered the study of NMD efficiency. Here, we develop an assay to visualize NMD of individual mRNA molecules in real time. We find that NMD occurs with equal probability during each round of translation of an mRNA molecule. However, this probability is variable and depends on the exon sequence downstream of the PTC, the PTC-to-intron distance, and the number of introns both upstream and downstream of the PTC. Additionally, a subpopulation of mRNAs can escape NMD, further contributing to variation in NMD efficiency. Our study uncovers real-time dynamics of NMD, reveals key mechanisms that influence NMD efficiency, and provides a powerful method to study NMD.

Originele taal-2Engels
Pagina's (van-tot)324-339.e11
TijdschriftMolecular Cell
Volume75
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - 25 jul 2019

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