CRISPR Cas12a3: A precise tool to halt viral protein production

Across all domains of life, immune defenses foil invading viruses by making it impossible for the viruses to replicate. Most known CRISPR systems target invading pathogens' DNA and chop it up to disable and modify genes, heading off infections at the (cellular) pass.

Utah State University chemist Ryan Jackson and his students study two lesser known CRISPR (Clustered regularly interspaced short palindromic repeats) systems known as Cas12a2 and Cas12a3. In contrast to the better known CRISPR-Cas9, which uses a guide RNA to locate a specific DNA sequence, Cas12a2 and Cas12a3 directly target RNA.

We're very focused on the basic research of understanding the structure and function of the CRISPR systems we study, and helping researchers around the world work through bottlenecks that enable them to pursue therapeutic applications."

Jackson, R. Gaurth Hansen, Associate Professor in USU's Department of Chemistry and Biochemistry

With doctoral student Kadin Crosby and master's student Bamidele Filani, Jackson, along collaborators in Europe, reports new findings about CRISPR-Cas12a3 in the January 7, 2026 issue of the journal Nature. These discoveries could lead to more efficient and accurate diagnostic tools to rapidly detect COVID, influenza and RSV infections, individually or in combination, with a single test, in a single patient.

Jackson and his team are learning more about Cas12a2 and Cas12a3's distinctive characteristics.

"Instead of making a single break in the bound target, as Cas9 does to DNA, RNA target binding by Cas12a2 and Cas12a3 changes the shape of a protein in a way that activates them to cut another nucleic acid target over and over again," he says. "When activated, Cas12a2 indiscriminately cleaves DNA, destroying all viral DNA, but collaterally killing the host cell as well. In contrast, Cas12a3 cleaves transfer ribonucleic acids, known as tRNAs, halting virus protein production, while sparing the DNA of host cells."

That latter ability enables Cas12a3 to target tRNA is a very precise way. Jackson and his team are trying to harness that ability to detect and target specific pathogens.

"tRNA is the lynchpin of protein synthesis," Jackson says. "It functions as a translation device that can read code on RNA and act as a molecular bridge to link that code to the correct amino acid to allow protein production."

Cas12a3 has the ability to disable tRNA's translation ability.

"Cas12a3 can stop protein production in its tracks by chopping off a specific region of tRNA, called the 'tail,' which contains the amino acid," he says. "This is a very powerful and precise way to prevent a pathogen, including a virus, from replicating in a cell, without damaging the cell's DNA."

Jackson says Cas12a3's ability to cleave tRNA tails is a newly discovered CRISPR immune response.

"We think being able to stop an invading pathogen, while leaving DNA unchanged could be a therapeutic breakthrough," he says. "As we study these systems, we're also discovering the enormous functional diversity in these bacterial defense mechanisms."

Jackson adds Crosby and Filani played key roles in discovering and defining the specific functions of Cas12a3, and determining its ability to perform as a diagnostic tool.

Collaborators on the study include Chase Beisel at Germany's Helmholtz Institute for RNA-based Infection Research in Würzburg and Dirk Heinz at the Helmholtz Center for Infection Research in Braunschweig, along with researchers at Jagiellonian University in Poland, the University of Strasbourg in France, the Freie University in Germany, the Robert Koch Institute in Germany, the University of Veterinary Medicine Austria and the Institute of Science and Technology Austria.

Jackson and his students' research is supported by the R. Gaurth Hansen Family and the National Institutes of Health.