Researchers at Utah State University, led by chemist Ryan Jackson, have published findings detailing the mechanism of the CRISPR-Cas12a3 system. The study, appearing in the January 7, 2026, issue of Nature, describes how Cas12a3 targets viral RNA and inhibits protein production by cleaving transfer ribonucleic acids (tRNAs) while preserving host cell DNA. This discovery suggests potential applications in diagnostics and therapeutics for viral infections.
Research Overview
The research focuses on CRISPR (Clustered regularly interspaced short palindromic repeats) systems, which function as immune defenses against viruses. While many CRISPR systems, such as CRISPR-Cas9, are known to target and cleave DNA, the Cas12a2 and Cas12a3 systems specifically target RNA. The investigation, conducted by Jackson, doctoral student Kadin Crosby, and master’s student Bamidele Filani, sought to clarify the distinct functions of these RNA-targeting mechanisms.
Distinct Mechanisms of Cas12a2 and Cas12a3
The study differentiates between the activation and effects of Cas12a2 and Cas12a3:
- Activation: Both Cas12a2 and Cas12a3 undergo a conformational change upon binding to their RNA target, which activates them to repeatedly cleave other nucleic acid targets.
- Cas12a2: When activated by RNA target binding, Cas12a2 indiscriminately cleaves DNA. This action disables viral DNA but also leads to the destruction of the host cell.
- Cas12a3: Upon activation through RNA target binding, Cas12a3 specifically cleaves transfer ribonucleic acids (tRNAs). This process halts the production of viral proteins while preserving the DNA of host cells.
Cas12a3's Action on tRNA
Cas12a3 achieves its effect by cleaving a specific region of tRNA, referred to as the 'tail,' which is responsible for carrying amino acids. Transfer ribonucleic acids (tRNAs) are essential molecular bridges in protein synthesis, translating RNA code into specific amino acids. By severing the tRNA tail, Cas12a3 disables the tRNA's translation ability, thereby preventing the synthesis of pathogen proteins. This mechanism has been identified as a newly recognized CRISPR immune response that can inhibit pathogen replication without altering cellular DNA.
Potential Applications
The precise tRNA-targeting ability of Cas12a3 is being investigated for various potential applications. These include:
- Diagnostic Tools: Development of diagnostic tools capable of detecting infections such as COVID-19, influenza, and RSV.
- Therapeutic Approaches: Exploration of potential therapeutic uses that could inhibit pathogen replication without causing damage to host cell DNA.
Research Team and Support
The research team from Utah State University included lead chemist Ryan Jackson, doctoral student Kadin Crosby, and master’s student Bamidele Filani. Collaborating institutions included:
- Helmholtz Institute for RNA-based Infection Research, WĂĽrzburg, Germany
- Helmholtz Center for Infection Research, Braunschweig, Germany
- Jagiellonian University, Poland
- University of Strasbourg, France
- Freie University, Germany
- Robert Koch Institute, Germany
- University of Veterinary Medicine Austria
- Institute of Science and Technology Austria
Funding for this research was provided by the R. Gaurth Hansen Family and the National Institutes of Health.