. 2022 Nov 23;185(24):4574-4586.e16.

doi: 10.1016/j.cell.2022.10.020.

Diverse virus-encoded CRISPR-Cas systems include streamlined genome editors

Basem Al-Shayeb¹, Petr Skopintsev², Katarzyna M Soczek², Elizabeth C Stahl², Zheng Li³, Evan Groover⁴, Dylan Smock⁵, Amy R Eggers⁶, Patrick Pausch⁶, Brady F Cress⁵, Carolyn J Huang⁶, Brian Staskawicz⁴, David F Savage⁷, Steven E Jacobsen⁸, Jillian F Banfield⁹, Jennifer A Doudna¹⁰

Affiliations

¹ Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Earth and Planetary Science, University of California, Berkeley, CA, USA; Department of Environmental Science, Policy and Management, University of California, Berkeley, CA, USA; University of Melbourne, Melbourne, Australia; Department of Chemistry, University of California, Berkeley, CA, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Gladstone Institutes, University of California, San Francisco, CA, USA.
² Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA.
³ Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, USA.
⁴ Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, CA, USA.
⁵ Innovative Genomics Institute, University of California, Berkeley, CA, USA.
⁶ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁷ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
⁸ Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, USA; Howard Hughes Medical Institute, University of California, Los Angeles, CA, USA.
⁹ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Earth and Planetary Science, University of California, Berkeley, CA, USA; Department of Environmental Science, Policy and Management, University of California, Berkeley, CA, USA; University of Melbourne, Melbourne, Australia. Electronic address: jbanfield@berkeley.edu.
¹⁰ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, CA, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Gladstone Institutes, University of California, San Francisco, CA, USA. Electronic address: doudna@berkeley.edu.

PMID: 36423580
DOI: 10.1016/j.cell.2022.10.020

Free article

Diverse virus-encoded CRISPR-Cas systems include streamlined genome editors

Basem Al-Shayeb et al. Cell. 2022.

Free article

. 2022 Nov 23;185(24):4574-4586.e16.

doi: 10.1016/j.cell.2022.10.020.

Authors

Affiliations

¹ Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Earth and Planetary Science, University of California, Berkeley, CA, USA; Department of Environmental Science, Policy and Management, University of California, Berkeley, CA, USA; University of Melbourne, Melbourne, Australia; Department of Chemistry, University of California, Berkeley, CA, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Gladstone Institutes, University of California, San Francisco, CA, USA.
² Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA.
³ Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, USA.
⁴ Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, CA, USA.
⁵ Innovative Genomics Institute, University of California, Berkeley, CA, USA.
⁶ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁷ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
⁸ Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, USA; Howard Hughes Medical Institute, University of California, Los Angeles, CA, USA.
⁹ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Earth and Planetary Science, University of California, Berkeley, CA, USA; Department of Environmental Science, Policy and Management, University of California, Berkeley, CA, USA; University of Melbourne, Melbourne, Australia. Electronic address: jbanfield@berkeley.edu.
¹⁰ Innovative Genomics Institute, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, CA, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Gladstone Institutes, University of California, San Francisco, CA, USA. Electronic address: doudna@berkeley.edu.

PMID: 36423580
DOI: 10.1016/j.cell.2022.10.020

Abstract

CRISPR-Cas systems are host-encoded pathways that protect microbes from viral infection using an adaptive RNA-guided mechanism. Using genome-resolved metagenomics, we find that CRISPR systems are also encoded in diverse bacteriophages, where they occur as divergent and hypercompact anti-viral systems. Bacteriophage-encoded CRISPR systems belong to all six known CRISPR-Cas types, though some lack crucial components, suggesting alternate functional roles or host complementation. We describe multiple new Cas9-like proteins and 44 families related to type V CRISPR-Cas systems, including the Casλ RNA-guided nuclease family. Among the most divergent of the new enzymes identified, Casλ recognizes double-stranded DNA using a uniquely structured CRISPR RNA (crRNA). The Casλ-RNA-DNA structure determined by cryoelectron microscopy reveals a compact bilobed architecture capable of inducing genome editing in mammalian, Arabidopsis, and hexaploid wheat cells. These findings reveal a new source of CRISPR-Cas enzymes in phages and highlight their value as genome editors in plant and human cells.

Keywords: CRISPR; CRISPR-Cas; anti-viral; enzyme; genome editing; genome editor; metagenomics; phage; structure; tool.

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Conflict of interest statement

Declaration of interests The Regents of the University of California have filed patents related to this work on which the authors are inventors. J.A.D. is a co-founder of Caribou Biosciences, Editas Medicine, Scribe Therapeutics, Intellia Therapeutics, and Mammoth Biosciences. J.A.D. is a scientific advisory board member of Vertex, Caribou Biosciences, Intellia Therapeutics, Scribe Therapeutics, Mammoth Biosciences, Algen Biotechnologies, Felix Biosciences, The Column Group, and Inari Agriculture. J.A.D. is Chief Science Advisor to Sixth Street, a Director at Johnson & Johnson, and Altos and Tempus, and has research projects sponsored by Apple Tree Partners and Roche. J.F.B. is a co-founder of Metagenomi. S.E.J. is a scientific co-founder of Inari Agriculture, and a science advisory board member to Invaio Sciences, Senda Biosciences, FL70, and Sixth Street.

Comment in

CRISPR tools found in thousands of viruses could boost gene editing.
Ledford H. Ledford H. Nature. 2022 Dec;612(7938):21. doi: 10.1038/d41586-022-03837-8. Nature. 2022. PMID: 36418881 No abstract available.
CRISPR inspirations from nature.
Hua H. Hua H. Nat Methods. 2023 Jan;20(1):37. doi: 10.1038/s41592-022-01756-0. Nat Methods. 2023. PMID: 36635554 No abstract available.

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Diverse virus-encoded CRISPR-Cas systems include streamlined genome editors

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Diverse virus-encoded CRISPR-Cas systems include streamlined genome editors

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Abstract

Conflict of interest statement

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