Compact Cas9d and HEARO enzymes for genome editing discovered from uncultivated microbes

Daniela S. Aliaga Goltsman (), Lisa M. Alexander, Jyun-Liang Lin, Rodrigo Fregoso Ocampo, Benjamin Freeman, Rebecca C. Lamothe, Andres Perez Rivas, Morayma M. Temoche-Diaz, Shailaja Chadha, Natalie Nordenfelt, Owen P. Janson, Ian Barr, Audra E. Devoto, Gregory J. Cost, Cristina N. Butterfield, Brian C. Thomas and Christopher T. Brown ()
Additional contact information
Daniela S. Aliaga Goltsman: Metagenomi Inc. 1545 Park Ave
Lisa M. Alexander: Metagenomi Inc. 1545 Park Ave
Jyun-Liang Lin: Metagenomi Inc. 1545 Park Ave
Rodrigo Fregoso Ocampo: Metagenomi Inc. 1545 Park Ave
Benjamin Freeman: Metagenomi Inc. 1545 Park Ave
Rebecca C. Lamothe: Metagenomi Inc. 1545 Park Ave
Andres Perez Rivas: Metagenomi Inc. 1545 Park Ave
Morayma M. Temoche-Diaz: Metagenomi Inc. 1545 Park Ave
Shailaja Chadha: Metagenomi Inc. 1545 Park Ave
Natalie Nordenfelt: Metagenomi Inc. 1545 Park Ave
Owen P. Janson: Metagenomi Inc. 1545 Park Ave
Ian Barr: Metagenomi Inc. 1545 Park Ave
Audra E. Devoto: Metagenomi Inc. 1545 Park Ave
Gregory J. Cost: Metagenomi Inc. 1545 Park Ave
Cristina N. Butterfield: Metagenomi Inc. 1545 Park Ave
Brian C. Thomas: Metagenomi Inc. 1545 Park Ave
Christopher T. Brown: Metagenomi Inc. 1545 Park Ave

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Programmable, RNA-guided nucleases are diverse enzymes that have been repurposed for biotechnological applications. However, to further expand the therapeutic application of these tools there is a need for targetable systems that are small enough to be delivered efficiently. Here, we mined an extensive genome-resolved metagenomics database and identified families of uncharacterized RNA-guided, compact nucleases (between 450 and 1,050 aa). We report that Cas9d, a new CRISPR type II subtype, contains Zinc-finger motifs and high arginine content, features that we also found in nucleases related to HEARO effectors. These enzymes exhibit diverse biochemical characteristics and are broadly targetable. We show that natural Cas9d enzymes are capable of genome editing in mammalian cells with >90% efficiency, and further engineered nickase variants into the smallest base editors active in E. coli and human cells. Their small size, broad targeting potential, and translatability suggest that Cas9d and HEARO systems will enable a variety of genome editing applications.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-35257-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35257-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-35257-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().