Cas12a2 elicits abortive infection through RNA-triggered destruction of dsDNA

Oleg Dmytrenko, Gina C. Neumann, Thomson Hallmark, Dylan J. Keiser, Valerie M. Crowley, Elena Vialetto, Ioannis Mougiakos, Katharina G. Wandera, Hannah Domgaard, Johannes Weber, Thomas Gaudin, Josie Metcalf, Benjamin N. Gray, Matthew B. Begemann (), Ryan N. Jackson () and Chase L. Beisel ()
Additional contact information
Oleg Dmytrenko: Helmholtz Centre for Infection Research
Gina C. Neumann: Benson Hill
Thomson Hallmark: Utah State University
Dylan J. Keiser: Utah State University
Valerie M. Crowley: Utah State University
Elena Vialetto: Helmholtz Centre for Infection Research
Ioannis Mougiakos: Helmholtz Centre for Infection Research
Katharina G. Wandera: Helmholtz Centre for Infection Research
Hannah Domgaard: Utah State University
Johannes Weber: Helmholtz Centre for Infection Research
Thomas Gaudin: Helmholtz Centre for Infection Research
Josie Metcalf: Utah State University
Benjamin N. Gray: Benson Hill
Matthew B. Begemann: Benson Hill
Ryan N. Jackson: Utah State University
Chase L. Beisel: Helmholtz Centre for Infection Research

Nature, 2023, vol. 613, issue 7944, 588-594

Abstract: Abstract Bacterial abortive-infection systems limit the spread of foreign invaders by shutting down or killing infected cells before the invaders can replicate1,2. Several RNA-targeting CRISPR–Cas systems (that is, types III and VI) cause abortive-infection phenotypes by activating indiscriminate nucleases3–5. However, a CRISPR-mediated abortive mechanism that leverages indiscriminate DNase activity of an RNA-guided single-effector nuclease has yet to be observed. Here we report that RNA targeting by the type V single-effector nuclease Cas12a2 drives abortive infection through non-specific cleavage of double-stranded DNA (dsDNA). After recognizing an RNA target with an activating protospacer-flanking sequence, Cas12a2 efficiently degrades single-stranded RNA (ssRNA), single-stranded DNA (ssDNA) and dsDNA. Within cells, the activation of Cas12a2 induces an SOS DNA-damage response and impairs growth, preventing the dissemination of the invader. Finally, we harnessed the collateral activity of Cas12a2 for direct RNA detection, demonstrating that Cas12a2 can be repurposed as an RNA-guided RNA-targeting tool. These findings expand the known defensive abilities of CRISPR–Cas systems and create additional opportunities for CRISPR technologies.

Date: 2023
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DOI: 10.1038/s41586-022-05559-3

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