Broad-spectrum enzymatic inhibition of CRISPR-Cas12a
Abstract
Cas12a is a bacterial RNA-guided nuclease used widely for genome editing and, more recently, as a molecular diagnostic. In bacteria, Cas12a enzymes can be inhibited by bacteriophage-derived proteins, anti-CRISPRs (Acrs), to thwart clustered regularly interspaced short palindromic repeat (CRISPR) adaptive immune systems. How these inhibitors disable Cas12a by preventing programmed DNA cleavage is unknown. We show that three such inhibitors (AcrVA1, AcrVA4 and AcrVA5) block Cas12a activity via functionally distinct mechanisms, including a previously unobserved enzymatic strategy. AcrVA4 and AcrVA5 inhibit recognition of double-stranded DNA (dsDNA), with AcrVA4 driving dimerization of Cas12a. In contrast, AcrVA1 is a multiple-turnover inhibitor that triggers cleavage of the target-recognition sequence of the Cas12a-bound guide RNA to irreversibly inactivate the Cas12a complex. Finally, these distinct mechanisms equip bacteriophages with tools to evade CRISPR-Cas12a and support biotechnological applications for which multiple-turnover enzymatic inhibition of Cas12a is desirable.
- Authors:
-
- Univ. of California, Berkeley, CA (United States)
- Univ. of California, Berkeley, CA (United States). Howard Hughes Medical Inst. and Innovative Genomics Inst. ; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Gladstone Inst., San Francisco, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1605236
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Structural & Molecular Biology
- Additional Journal Information:
- Journal Volume: 26; Journal Issue: 4; Journal ID: ISSN 1545-9993
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Knott, Gavin J., Thornton, Brittney W., Lobba, Marco J., Liu, Jun-Jie, Al-Shayeb, Basem, Watters, Kyle E., and Doudna, Jennifer A. Broad-spectrum enzymatic inhibition of CRISPR-Cas12a. United States: N. p., 2019.
Web. doi:10.1038/s41594-019-0208-z.
Knott, Gavin J., Thornton, Brittney W., Lobba, Marco J., Liu, Jun-Jie, Al-Shayeb, Basem, Watters, Kyle E., & Doudna, Jennifer A. Broad-spectrum enzymatic inhibition of CRISPR-Cas12a. United States. https://doi.org/10.1038/s41594-019-0208-z
Knott, Gavin J., Thornton, Brittney W., Lobba, Marco J., Liu, Jun-Jie, Al-Shayeb, Basem, Watters, Kyle E., and Doudna, Jennifer A. Mon .
"Broad-spectrum enzymatic inhibition of CRISPR-Cas12a". United States. https://doi.org/10.1038/s41594-019-0208-z. https://www.osti.gov/servlets/purl/1605236.
@article{osti_1605236,
title = {Broad-spectrum enzymatic inhibition of CRISPR-Cas12a},
author = {Knott, Gavin J. and Thornton, Brittney W. and Lobba, Marco J. and Liu, Jun-Jie and Al-Shayeb, Basem and Watters, Kyle E. and Doudna, Jennifer A.},
abstractNote = {Cas12a is a bacterial RNA-guided nuclease used widely for genome editing and, more recently, as a molecular diagnostic. In bacteria, Cas12a enzymes can be inhibited by bacteriophage-derived proteins, anti-CRISPRs (Acrs), to thwart clustered regularly interspaced short palindromic repeat (CRISPR) adaptive immune systems. How these inhibitors disable Cas12a by preventing programmed DNA cleavage is unknown. We show that three such inhibitors (AcrVA1, AcrVA4 and AcrVA5) block Cas12a activity via functionally distinct mechanisms, including a previously unobserved enzymatic strategy. AcrVA4 and AcrVA5 inhibit recognition of double-stranded DNA (dsDNA), with AcrVA4 driving dimerization of Cas12a. In contrast, AcrVA1 is a multiple-turnover inhibitor that triggers cleavage of the target-recognition sequence of the Cas12a-bound guide RNA to irreversibly inactivate the Cas12a complex. Finally, these distinct mechanisms equip bacteriophages with tools to evade CRISPR-Cas12a and support biotechnological applications for which multiple-turnover enzymatic inhibition of Cas12a is desirable.},
doi = {10.1038/s41594-019-0208-z},
journal = {Nature Structural & Molecular Biology},
number = 4,
volume = 26,
place = {United States},
year = {Mon Apr 01 00:00:00 EDT 2019},
month = {Mon Apr 01 00:00:00 EDT 2019}
}
Web of Science
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