For several years now, the CRISPR/Cas9 gene scissors have been causing a sensation in science and medicine. This new molecular biology tool has its origins in an ancient bacterial immune system. It protects bacteria from attacks by so-called phages, that is, viruses that infect bacteria. Researchers from the Institute of Structural Biology at the University Hospital Bonn (UKB) and the Faculty of Medicine of the University of Bonn, in cooperation with the University of St Andrews in Scotland and the European Laboratory for Molecular Biology of ‘Hamburg, have now discovered a new function of the gene scissors. The study was published yesterday in the well-known scientific journal “Nature”.
Bacteria and phages have been engaged in a life-and-death struggle on Earth since time immemorial. When an attacking phage injects its genetic material into a bacterium, it is forced to produce new phages, which in turn infect more bacteria. Some bacteria have evolved the CRISPR system in response. With this bacterial immune system, the phage’s genetic material is recognized and destroyed.
At the same time, the resulting fragments are integrated into the genome of the bacterium. This creates a kind of library that the CRISPR immune system can access again and again and is therefore armed for future attacks. In addition, it was discovered that the so-called type III variants of gene scissors produce small signal molecules. With the help of these small molecules, the bacteria ignite a complex emergency plan. This ensures that a virus can be combated optimally and on a broad front.
Researchers at the Institute for Structural Biology at the University Hospital Bonn (UKB) and the Faculty of Medicine at the University of Bonn have now investigated how this works in cooperation with scientists at the University of St Andrews in Scotland and the Laboratory European Molecular Biology in Scotland. Hamburg. The research team discovered that the small signal molecules bind, among other things, to a protein called CalpL, which then becomes an active “protease”. These are enzymes that cut proteins and thus function as protein scissors. “Proteases are also used in the human immune system to transmit information at high speed,” says Niels Schneberger, a PhD student at UKB’s Institute of Structural Biology and one of the two first authors of the study.
Finally, the researchers also found the target of their newly discovered protein scissors. He cuts a small protein molecule called CalpT, which acts as a safety latch for CalpS, a third protein molecule: “CalpS is a very well-protected protein that is released throughout the mechanism. It will bring the transcription machinery to genes specific. , changing the bacterium’s metabolism to defense. We are very curious to know what these genes are,” explains Christophe Rouillon, who is a visiting scientist at the Institute of Structural Biology and first author of the study. With the discovery of this complicated signaling cascade, researchers have now discovered an entirely new aspect of CRISPR systems.
The great thing about CRISPR systems is also that they can be very easily reprogrammed for biotechnological and medical purposes. With the help of CRISPR, DNA can be specifically altered, that is, genes or entire blocks of genes can be inserted or removed. Some diseases, such as spinal muscular atrophy (SMA), which causes nerve paralysis, can already be treated today with the help of genetic scissors.
With these CRISPR-enabled protein scissors, there is now a whole new tool in the molecular biology toolbox. And perhaps this will allow CRISPR to be used in even more versatile ways in the future.”
P.S. Dr. Gregor Hagelueken, head of group at UKB’s Institute of Structural Biology and member of the Transdisciplinary Research Area “Life and Health” at the University of Bonn
Source:
University Hospital Bonn (UKB)
Journal reference:
Rouillon, C., et al. (2022) Antiviral signaling by a cyclic nucleotide-activated CRISPR protease. Nature. doi.org/10.1038/s41586-022-05571-7.