Discovery of a new function of the CRISPR gene scissors: the protein scissors activate the defense function

Discovery of a new function of the CRISPR gene scissors: the protein scissors activate the defense function

New function of the CRISPR gene scissors discovered: Protein scissors activate defense function Uncropped and unedited version of all gels used in this study. The red box indicates the portion of the gel that is shown in the indicated figures. Credit: Nature (2022). DOI: 10.1038/s41586-022-05571-7

For several years, the CRISPR/Cas9 gene scissors have caused a stir 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 (viruses that infect bacteria).

Researchers from the Institute for Structural Biology at the University Hospital Bonn (UKB) and the Faculty of Medicine of the University of Bonn, in cooperation with the partner University of St Andrews in Scotland and the European Biological Laboratory Molecular University of Hamburg, discovered a new function of gene scissors. The study was published in 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 genetic material of the phage 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 thus armed for future attacks. In addition, so-called type III variants of the scissor gene have been found to produce small signal molecules. With the help of these small molecules, the bacteria trigger a complex emergency plan. This ensures that a virus can be combated optimally and on a broad front.

Researchers from 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 it works in cooperation with scientists from the partner University of St Andrews in Scotland and the European Molecular Biology Laboratory in Hamburg. The research team discovered that the small signal molecules bind, among other things, to a protein called CalpL, which thus becomes an active “protease”.

These are enzymes that cleave proteins and thus work like protein scissors. “Proteases are also used in the human immune system to transmit information at high speed,” says Niels Schneberger, a PhD student at the UKB’s Institute for Structural Biology and one of the study’s first two authors.

Finally, the researchers also found the target for their newly discovered protein scissors. It cuts a small protein molecule called CalpT, which acts as a safety lock for CalpS, a third protein molecule: “CalpS is a very well guarded protein that is released by the whole mechanism. It will bring the transcription machinery to specific genes. , switch the metabolism of the bacterium towards defense. We are very curious [to know] what are these genes”, explains Christophe Rouillon, guest researcher at the Institute of Structural Biology and first author of the study.

With the discovery of this complicated signaling cascade, researchers have now uncovered a whole new aspect of CRISPR systems.

The advantage of 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 modified, i.e. genes or entire blocks of genes can be inserted or excised. Some diseases, such as spinal muscular atrophy (SMA), which leads to nerve palsy, can already be treated today using gene scissors.

“With these CRISPR-enabled protein scissors, there is now a whole new tool in the molecular biology toolkit,” says Dr Gregor Hagelueken, group leader at the UKB Institute of Structural Biology and fellow of the transdisciplinary research area “Life and Health” at the University of Bonn. “And maybe this will allow CRISPR to be used in even more versatile ways in the future,” he adds.

More information:
Christophe Rouillon et al, Antiviral signaling by a CRISPR protease activated by a cyclic nucleotide, Nature (2022). DOI: 10.1038/s41586-022-05571-7

Provided by University Hospital Bonn (UKB)

Quote: Discovery of a new function of CRISPR gene scissors: Protein scissors activate defense function (November 25, 2022) Retrieved on November 25, 2022 from https://phys.org/news/2022-11-function-crispr -gene-scissors-protein.html

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