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Updated: Jan 20, 2026
The Upf Proteins and Nonsense-mediated mRNA Decay
A role for DIS3L2 over natural nonsense-mediated mRNA decay targets in human cells
Paulo J da Costa1, Juliane Menezes1, Margarida Saramago2
1Department of Human Genetics, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI - Biosystems and Integrative Sciences Institute, Lisboa, Portugal.
Abstract:
The nonsense-mediated decay (NMD) pathway selectively degrades mRNAs carrying a premature translation-termination codon but also regulates the abundance of a large number of physiological mRNAs that encode full-length proteins. In human cells, NMD-targeted mRNAs are degraded by endonucleolytic cleavage and exonucleolytic degradation from both 5-' and 3'-ends. This is done by a process not yet completely understood that recruits decapping and 5'-to-3' exonuclease activities, as well as deadenylating and 3'-to-5' exonuclease exosome activities. In yeast, DIS3/Rrp44 protein is the catalytic subunit of the exosome, but in humans, there are three known paralogues of this enzyme: DIS3, DIS3L1, and DIS3L2. However, little is known about their role in NMD. Here, we show that some NMD-targets are DIS3L2 substrates in human cells. In addition, we observed that DIS3L2 acts over full-length transcripts, through a process that also involves UPF1. Moreover, DIS3L2-mediated decay is dependent on the activity of the terminal uridylyl transferases Zcchc6/11 (TUT7/4). Together, our findings establish a role for DIS3L2 and uridylation in NMD.
Insights
The nonsense-mediated decay (NMD) pathway degrades faulty mRNAs. This study reveals that DIS3L2 and uridylation are crucial for NMD regulation in human cells, impacting both aberrant and normal transcripts.
Area of Science:
- Molecular Biology
- RNA Biology
- Gene Regulation
Background:
- Nonsense-mediated decay (NMD) is a surveillance pathway that degrades mRNAs with premature termination codons.
- NMD also regulates the abundance of physiological mRNAs encoding full-length proteins.
- The human exosome complex, including DIS3, DIS3L1, and DIS3L2, plays a role in mRNA degradation, but their specific involvement in NMD is unclear.
Purpose of the Study:
- To investigate the role of human DIS3 paralogues, particularly DIS3L2, in the nonsense-mediated decay (NMD) pathway.
- To elucidate the mechanism by which DIS3L2 contributes to NMD.
- To determine the relationship between DIS3L2, uridylation, and NMD.
Main Methods:
- Analysis of NMD targets in human cells.
- Investigating the interaction and function of DIS3L2 in NMD.
- Assessing the dependence of DIS3L2-mediated decay on terminal uridylyl transferase (TUT) activity.
Main Results:
- Identified specific NMD targets as substrates for DIS3L2 in human cells.
- Demonstrated that DIS3L2 acts on full-length transcripts in a process involving UPF1.
- Showed that DIS3L2-mediated mRNA decay is dependent on the enzymatic activity of terminal uridylyl transferases Zcchc6/11 (TUT7/4).
Conclusions:
- Established a novel role for DIS3L2 as a key player in the nonsense-mediated decay (NMD) pathway.
- Highlighted the significance of uridylation, mediated by TUT7/4, in DIS3L2-dependent NMD.
- Expanded the understanding of mRNA surveillance and regulation mechanisms in human cells.
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