Cellular quality control in humans decoded

The process referred to as ‘nonsense-mediated mRNA decay’ (NMD) is responsible for quality control in all cells of the body. This process monitors messenger RNAs (mRNA), which carry the blueprints for proteins. If errors are detected, the cell eliminates these faulty blueprints before incomplete or harmful proteins can be produced that might trigger diseases such as developmental disorders or cancer. In their new study, the Cologne team led by Professor Dr Niels H. Gehring at the Institute for Genetics used molecular switches that allow the key molecule of NMD, the protein UPF1, to be selectively switched off at an exact point in time. This made it possible for the first time to observe the function of the NMD in human cells with unprecedented precision. The study ‘Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated human transcriptome’ was published in Molecular Cell.

A key outcome is the generation of a comprehensive database that, for the first time, systematically records which genes and gene variants are directly affected by NMD. This resource is available worldwide free of charge (https://nmdrht.uni-koeln.de) and opens up new avenues for RNA and genome research.

“Our new system makes it possible, for the first time, to understand how rapidly and comprehensively NMD acts in human cells. This shows that NMD not only provides protection against errors, but also acts an important regulator of gene activity,” says Gehring.

The scientists found that NMD follows fixed rules. If the blueprint for a protein contains a ‘stop signal’ in the wrong place, the cell recognizes this error and disposes of the blueprint, thus preventing the production of a useless or harmful protein.

“Thanks to the new system, we have found many new RNA variants that are regulated by NMD and had been previously overlooked. These include RNA variants that are involved in brain development,” adds Dr Volker Böhm, first author of the study. “The fact that there are so many variants is surprising. In the future, we will be analysing the reasons for this large number in greater detail. Until now, they have remained undetected in the absence of suitable analytical techniques. Our database will therefore be an important tool for genome research worldwide.”

“This result impressively demonstrates how new technologies enable the visualization of fundamental biological mechanisms that are of great importance for health and disease,” explains co-author Professor Markus Landthaler from the Max Delbrück Center in Berlin.

The study was carried out and financed as part of the Collaborative Research Centre CRC 1678 ‘Systems-level consequences of fidelity changes in mRNA and protein biosynthesis’ of the German Research Foundation (DFG) and is supported by the Center for Molecular Medicine Cologne (CMMC).