. Scientific Frontline: New kind of scissors discovered

Thursday, January 5, 2023

New kind of scissors discovered

Professor Chase Beisel and Dr. Oleg Dmytrenko in the Würzburg HIRI laboratory.
Photo Credit: HIRI

Like a Swiss Army knife: a newly discovered component of bacterial immune defense paralyzes infected cells. He could advance molecular biological diagnostics.

Bacteria can also be infected by viruses, and they have developed their own immune defense strategies in this case. Bacterial defense systems such as CRISPR-Cas have various proteins and functions that help the bacteria protect themselves against intruders.

The defense is based on a common basic mechanism: a CRISPR ribonucleic acid (crRNA), which serves as a "lead RNA", helps to identify regions of a foreign genome, such as the DNA of a virus, in order to make them specifically harmless. The nuclease led by a crRNA can cut its target like scissors. It is a strategy of nature that humans have made use of technologically in a variety of ways.

"When you consider how well different nucleases have been implemented in new and improved technologies, any discovery in this area could bring new benefits to society," Professor Chase Beisel describes a research motivation of his laboratory at the Helmholtz Institute for RNA-based in Würzburg Infection research (HIRI). The facility is a location of the Helmholtz Center for Infection Research in Braunschweig in cooperation with the Julius Maximilians University, to which Chase Beisel is the head of the chair for synthetic RNA biology.

A completely new way of preventing CRISPR immune systems

The researchers have now made an unexpected discovery. Chase Beisel has worked with Matthew Begemann from Benson Hill, Inc. (Missouri), and Ryan Jackson from Utah State University found a nuclease in the United States called Cas12a2, which represents a whole new way of preventing CRISPR immune. The results are in the journal Nature published. They are accompanied by a further structural analysis, which was carried out by a second team led by Ryan Jackson and David Taylor (University of Texas).

“We researched CRISPR nucleases that were originally subsumed under Cas12a, i.e. under nucleases that protect bacteria from intruders by recognizing and splitting invasive DNA. However, when we identified more of these nucleases, there were so many differences that it was worth going deeper into the matter,” reports Oleg Dmytrenko, first author of the study. “We discovered that these nucleases, which we called Cas12a2, not only behave very differently than Cas12a, but also as any other known CRISPR nuclease."

Unlike any other known CRISPR nuclease

The crucial difference: If Cas12a2 detects invasive RNA, the nuclease splits it, but can also damage other RNA and DNA in the cell. This affects their growth and insulates the infection. Basically, such so-called abortive infection defense strategies (abi) of bacteria are already known, says HIRI-Postdoc Dmytrenko.

Some other CRISPR cas systems also worked in this way. "However, a CRISPR-based defense mechanism based on a single nuclease to recognize the intruder and break down cellular DNA and RNA has never been observed," the scientist says. Cas12a2 can be used for molecular diagnostics and the direct detection of RNA biomarkers, as proof of feasibility has shown.

Funding

The study was funded by the European Research Council (ERC Consolidator Grant to Chase Beisel), the Federal Agency for Jump Innovation (SPRIND), the Pre-4D program of the Helmholtz Center for Infection Research and the National Institutes of Health and the Welch Foundation.

Published in journalNature

Research MaterialUniversity of Texas at Austin study

Source/CreditUniversity of Würzburg

Reference Number: bio010523_02

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