SCOPE enables type III CRISPR-Cas diagnostics using flexible targeting and stringent CARF ribonuclease activation

Jurre A. Steens, Yifan Zhu (), David W. Taylor, Jack P. K. Bravo, Stijn H. P. Prinsen, Cor D. Schoen, Bart J. F. Keijser, Michel Ossendrijver, L. Marije Hofstra, Stan J. J. Brouns, Akeo Shinkai, John Oost and Raymond H. J. Staals ()
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Jurre A. Steens: Wageningen University and Research
Yifan Zhu: Wageningen University and Research
David W. Taylor: University of Texas at Austin
Jack P. K. Bravo: University of Texas at Austin
Stijn H. P. Prinsen: Scope Biosciences
Cor D. Schoen: Wageningen Plant Research
Bart J. F. Keijser: TNO
Michel Ossendrijver: TNO
L. Marije Hofstra: University Medical Center Utrecht
Stan J. J. Brouns: Delft University of Technology
Akeo Shinkai: RIKEN SPring-8 Center, Sayo
John Oost: Wageningen University and Research
Raymond H. J. Staals: Wageningen University and Research

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Characteristic properties of type III CRISPR-Cas systems include recognition of target RNA and the subsequent induction of a multifaceted immune response. This involves sequence-specific cleavage of the target RNA and production of cyclic oligoadenylate (cOA) molecules. Here we report that an exposed seed region at the 3′ end of the crRNA is essential for target RNA binding and cleavage, whereas cOA production requires base pairing at the 5′ end of the crRNA. Moreover, we uncover that the variation in the size and composition of type III complexes within a single host results in variable seed regions. This may prevent escape by invading genetic elements, while controlling cOA production tightly to prevent unnecessary damage to the host. Lastly, we use these findings to develop a new diagnostic tool, SCOPE, for the specific detection of SARS-CoV-2 from human nasal swab samples, revealing sensitivities in the atto-molar range.

Date: 2021
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DOI: 10.1038/s41467-021-25337-5

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