RNA (New York, N.Y.)Aug 22, 2013

Two partly overlapping pathways for breaking down faulty messenger RNA in human cells, with and without EJC involvement

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

Both EJC-enhanced and EJC-independent modes of nonsense-mediated mRNA decay (NMD) require UPF1 and SMG1.

Transcript-specific differences were observed in the requirement for UPF2 and UPF3b between the two NMD modes.
EJC-independent NMD demonstrated higher sensitivity to reduced concentrations of UPF2 and UPF3b.
A redundancy of endo- and exonucleolytic mRNA degradation pathways was identified in both NMD modes.
The decay pathways contributed differently to the degradation of mRNA transcripts, with immunoglobulin μ being more affected by SMG6-mediated cleavage and β-Globin primarily degraded by the SMG5/SMG7 pathway.
The findings indicate the presence of several distinct branches of NMD in human cells.

Simplified

Nonsense-mediated mRNA decay (NMD) is a eukaryotic post-transcriptional gene regulation mechanism that eliminates mRNAs with the termination codon (TC) located in an unfavorable environment for efficient translation termination. The best-studied NMD-targeted mRNAs contain premature termination codons (PTCs); however, NMD regulates even many physiological mRNAs. An exon-junction complex (EJC) located downstream from a TC acts as an NMD-enhancing signal, but is not generally required for NMD. Here, we compared these "EJC-enhanced" and "EJC-independent" modes of NMD with regard to their requirement for seven known NMD factors in human cells using two well-characterized NMD reporter genes (immunoglobulin μ and β-Globin) with or without an intron downstream from the PTC. We show that both NMD modes depend on UPF1 and SMG1, but detected transcript-specific differences with respect to the requirement for UPF2 and UPF3b, consistent with previously reported UPF2- and UPF3-independent branches of NMD. In addition and contrary to expectation, a higher sensitivity of EJC-independent NMD to reduced UPF2 and UPF3b concentrations was observed. Our data further revealed a redundancy of the endo- and exonucleolytic mRNA degradation pathways in both modes of NMD. Moreover, the relative contributions of both decay pathways differed between the reporters, with PTC-containing immunoglobulin μ transcripts being preferentially subjected to SMG6-mediated endonucleolytic cleavage, whereas β-Globin transcripts were predominantly degraded by the SMG5/SMG7-dependent pathway. Overall, the surprising heterogeneity observed with only two NMD reporter pairs suggests the existence of several mechanistically distinct branches of NMD in human cells.

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Two partly overlapping pathways for breaking down faulty messenger RNA in human cells, with and without EJC involvement

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