Nonsense-mediated mRNA decay (NMD) is one of the most important processes in our cells to ensure that no faulty or incomplete proteins are produced. Scientists have now identified a central mechanism behind this control system. The first step in protein production is the copying of the blueprint from the DNA, the mRNA. NMD checks mRNA for errors and specifically removes faulty transcripts. The most important factors of NMD have been known for some time, including the proteins SMG5 and SMG6. It is still unclear how the crucial cleavage of the faulty mRNA is activated. A research team at the University of Cologne led by Professor Dr Niels Gehring from the Institute for Genetics, together with the working group of Professor Dr Elena Conti from the Max Planck Institute of Biochemistry in Martinsried, has now shown that SMG5 and SMG6 interact directly with each other and together form an endonuclease – a molecular ‘pair of scissors’ – that cuts through RNA in a targeted manner. The study ‘Composite SMG5-SMG6 PIN domain formation is essential for NMD’ was published in the journal Nature Communications .
In itself, SMG6 is only weakly active as an endonuclease, SMG5 alone has no cutting activity. Only the interaction of both proteins produces a fully active enzyme. “We had already known the individual pieces of this mechanism puzzle for around 20 years, but we didn’t know how they fit together,” explains Gehring. “Thanks to the close collaboration with the Max Planck Institute of Biochemistry, we have succeeded in understanding the overall picture.” “It is astonishing that two proteins that are not very efficient on their own can develop such a strong increase in activity together,” says Sophie Theunissen, one of the first authors of the study. “Their combination creates a really hyperactive nuclease.”
The results not only provide a structural explanation for earlier observations, but also illustrate how precisely the NMD process needs to be regulated. “The activity of the NMD must be controlled with extreme spatial and temporal precision,” emphasizes Volker Böhm, one of the authors. “If the endonuclease were permanently fully active, it could cause considerable collateral damage to mRNAs that are actually normal. The complex activation by two separate proteins could represent precisely this safety mechanism.”
The work was carried out as part of the Collaborative Research Centre CRC 1678 ‘Systems-level consequences of fidelity changes in mRNA and protein biosynthesis’ funded by the German Research Foundation. With the recently published study, the Cologne team has made a fundamental contribution to the understanding of molecular quality control in human cells. As changes in the NMD system are associated with various diseases, the work provides an important basis for future biomedical research.
Nature Communications
Experimental study
Cells
Composite SMG5-SMG6 PIN domain formation is essential for NMD
19-Feb-2026