CasX enzymes comprise a distinct family of RNA-guided genome editors

Jun-Jie Liu, Natalia Orlova, Benjamin L. Oakes, Enbo Ma, Hannah B. Spinner, Katherine L. M. Baney, Jonathan Chuck, Dan Tan, Gavin J. Knott, Lucas B. Harrington, Basem Al-Shayeb, Alexander Wagner, Julian Brötzmann, Brett T. Staahl, Kian L. Taylor, John Desmarais, Eva Nogales () and Jennifer A. Doudna ()
Additional contact information
Jun-Jie Liu: University of California
Natalia Orlova: University of California
Benjamin L. Oakes: University of California
Enbo Ma: University of California
Hannah B. Spinner: University of California
Katherine L. M. Baney: University of California
Jonathan Chuck: University of California
Dan Tan: Salk Institute for Biological Studies
Gavin J. Knott: University of California
Lucas B. Harrington: University of California
Basem Al-Shayeb: University of California
Alexander Wagner: Max-Planck-Institute for Biochemistry
Julian Brötzmann: Ludwig-Maximilians-University
Brett T. Staahl: University of California
Kian L. Taylor: University of California
John Desmarais: University of California
Eva Nogales: University of California
Jennifer A. Doudna: University of California

Nature, 2019, vol. 566, issue 7743, 218-223

Abstract: Abstract The RNA-guided CRISPR-associated (Cas) proteins Cas9 and Cas12a provide adaptive immunity against invading nucleic acids, and function as powerful tools for genome editing in a wide range of organisms. Here we reveal the underlying mechanisms of a third, fundamentally distinct RNA-guided genome-editing platform named CRISPR–CasX, which uses unique structures for programmable double-stranded DNA binding and cleavage. Biochemical and in vivo data demonstrate that CasX is active for Escherichia coli and human genome modification. Eight cryo-electron microscopy structures of CasX in different states of assembly with its guide RNA and double-stranded DNA substrates reveal an extensive RNA scaffold and a domain required for DNA unwinding. These data demonstrate how CasX activity arose through convergent evolution to establish an enzyme family that is functionally separate from both Cas9 and Cas12a.

Date: 2019
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DOI: 10.1038/s41586-019-0908-x

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