Nonsense‑mediated mRNA decay (NMD) is one of the essential quality control processes in human cells, preventing the production of faulty or incomplete proteins. NMD inspects messenger RNA (mRNA)—the transient copy of genetic instructions—to detect and eliminate defective transcripts before they are translated into proteins. Although the principal components of NMD have been known for years, scientists had not yet clarified how the critical RNA‑cleaving step is activated.
Researchers led by Professor Niels Gehring at the University of Cologne’s Institute for Genetics, working with Professor Elena Conti’s team at the Max Planck Institute of Biochemistry in Martinsried, have now uncovered how this activation occurs. Their study, published in Nature Communications, shows that two proteins, SMG5 and SMG6, interact directly to form a single functioning endonuclease—a molecular “pair of scissors” capable of cutting through defective RNA molecules.
Earlier research had established that SMG6 has only weak activity as an endonuclease, while SMG5 has none. The new findings reveal that when the two proteins come together, they create a fully active enzyme that drives NMD’s precision cutting step. “We had already known the individual pieces of this mechanism puzzle for around 20 years, but we didn’t know how they fit together,” explained Gehring.
“It is astonishing that two proteins that are not very efficient on their own can develop such a strong increase in activity together,” said Sophie Theunissen, one of the first authors of the study. “Their combination creates a really hyperactive nuclease.”
Co‑author Volker Böhm emphasized that “the activity of the NMD must be controlled with extreme spatial and temporal precision.” If the enzyme complex were active continuously, it could inadvertently degrade normal mRNAs. The requirement for two separate proteins to form the active enzyme likely serves as a protective switch, preventing unintended damage within the cell.
Publication details: Kurscheidt, K., Theunissen, S., Pasquali, N. et al. Composite SMG5-SMG6 PIN domain formation is essential for NMD. Nat Commun 17, 1934 (2026). https://doi.org/10.1038/s41467-026-69819-w
Researchers led by Professor Niels Gehring at the University of Cologne’s Institute for Genetics, working with Professor Elena Conti’s team at the Max Planck Institute of Biochemistry in Martinsried, have now uncovered how this activation occurs. Their study, published in Nature Communications, shows that two proteins, SMG5 and SMG6, interact directly to form a single functioning endonuclease—a molecular “pair of scissors” capable of cutting through defective RNA molecules.
Earlier research had established that SMG6 has only weak activity as an endonuclease, while SMG5 has none. The new findings reveal that when the two proteins come together, they create a fully active enzyme that drives NMD’s precision cutting step. “We had already known the individual pieces of this mechanism puzzle for around 20 years, but we didn’t know how they fit together,” explained Gehring.
“It is astonishing that two proteins that are not very efficient on their own can develop such a strong increase in activity together,” said Sophie Theunissen, one of the first authors of the study. “Their combination creates a really hyperactive nuclease.”
Co‑author Volker Böhm emphasized that “the activity of the NMD must be controlled with extreme spatial and temporal precision.” If the enzyme complex were active continuously, it could inadvertently degrade normal mRNAs. The requirement for two separate proteins to form the active enzyme likely serves as a protective switch, preventing unintended damage within the cell.
Publication details: Kurscheidt, K., Theunissen, S., Pasquali, N. et al. Composite SMG5-SMG6 PIN domain formation is essential for NMD. Nat Commun 17, 1934 (2026). https://doi.org/10.1038/s41467-026-69819-w