Journal
NATURE
Volume 566, Issue 7743, Pages 218-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-019-0908-x
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Funding
- National Science Foundation [1244557]
- National Institutes of Health [P50GM082250]
- National Institute of General Medical Sciences of the National Institutes of Health [P01GM051487]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1244557] Funding Source: National Science Foundation
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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.
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