{"pmid":1,"title":"RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2","year":"2023","type":"journal_article","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"issue":"7944","scopus_import":"1","volume":613,"_id":"15130","date_updated":"2024-06-04T06:30:59Z","publication_status":"published","day":"04","month":"01","doi":"10.1038/s41586-022-05560-w","publisher":"Springer Nature","date_created":"2024-03-20T10:41:36Z","quality_controlled":"1","intvolume":"       613","extern":"1","oa_version":"Published Version","page":"582-587","date_published":"2023-01-04T00:00:00Z","publication":"Nature","status":"public","main_file_link":[{"url":"https://doi.org/10.1038/s41586-022-05560-w","open_access":"1"}],"article_type":"original","abstract":[{"lang":"eng","text":"Cas12a2 is a CRISPR-associated nuclease that performs RNA-guided, sequence-nonspecific degradation of single-stranded RNA, single-stranded DNA and double-stranded DNA following recognition of a complementary RNA target, culminating in abortive infection<jats:sup>1</jats:sup>. Here we report structures of Cas12a2 in binary, ternary and quaternary complexes to reveal a complete activation pathway. Our structures reveal that Cas12a2 is autoinhibited until binding a cognate RNA target, which exposes the RuvC active site within a large, positively charged cleft. Double-stranded DNA substrates are captured through duplex distortion and local melting, stabilized by pairs of ‘aromatic clamp’ residues that are crucial for double-stranded DNA degradation and in vivo immune system function. Our work provides a structural basis for this mechanism of abortive infection to achieve population-level immunity, which can be leveraged to create rational mutants that degrade a spectrum of collateral substrates."}],"citation":{"apa":"Bravo, J. P. K., Hallmark, T., Naegle, B., Beisel, C. L., Jackson, R. N., &#38; Taylor, D. W. (2023). RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2. <i>Nature</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41586-022-05560-w\">https://doi.org/10.1038/s41586-022-05560-w</a>","mla":"Bravo, Jack Peter Kelly, et al. “RNA Targeting Unleashes Indiscriminate Nuclease Activity of CRISPR–Cas12a2.” <i>Nature</i>, vol. 613, no. 7944, Springer Nature, 2023, pp. 582–87, doi:<a href=\"https://doi.org/10.1038/s41586-022-05560-w\">10.1038/s41586-022-05560-w</a>.","short":"J.P.K. Bravo, T. Hallmark, B. Naegle, C.L. Beisel, R.N. Jackson, D.W. Taylor, Nature 613 (2023) 582–587.","ieee":"J. P. K. Bravo, T. Hallmark, B. Naegle, C. L. Beisel, R. N. Jackson, and D. W. Taylor, “RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2,” <i>Nature</i>, vol. 613, no. 7944. Springer Nature, pp. 582–587, 2023.","chicago":"Bravo, Jack Peter Kelly, Thomson Hallmark, Bronson Naegle, Chase L. Beisel, Ryan N. Jackson, and David W. Taylor. “RNA Targeting Unleashes Indiscriminate Nuclease Activity of CRISPR–Cas12a2.” <i>Nature</i>. Springer Nature, 2023. <a href=\"https://doi.org/10.1038/s41586-022-05560-w\">https://doi.org/10.1038/s41586-022-05560-w</a>.","ista":"Bravo JPK, Hallmark T, Naegle B, Beisel CL, Jackson RN, Taylor DW. 2023. RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2. Nature. 613(7944), 582–587.","ama":"Bravo JPK, Hallmark T, Naegle B, Beisel CL, Jackson RN, Taylor DW. RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2. <i>Nature</i>. 2023;613(7944):582-587. doi:<a href=\"https://doi.org/10.1038/s41586-022-05560-w\">10.1038/s41586-022-05560-w</a>"},"publication_identifier":{"eissn":["1476-4687"],"issn":["0028-0836"]},"author":[{"first_name":"Jack Peter Kelly","last_name":"Bravo","full_name":"Bravo, Jack Peter Kelly","id":"96aecfa5-8931-11ee-af30-aa6a5d6eee0e","orcid":"0000-0003-0456-0753"},{"first_name":"Thomson","last_name":"Hallmark","full_name":"Hallmark, Thomson"},{"full_name":"Naegle, Bronson","last_name":"Naegle","first_name":"Bronson"},{"last_name":"Beisel","first_name":"Chase L.","full_name":"Beisel, Chase L."},{"full_name":"Jackson, Ryan N.","last_name":"Jackson","first_name":"Ryan N."},{"full_name":"Taylor, David W.","first_name":"David W.","last_name":"Taylor"}],"article_processing_charge":"Yes (in subscription journal)","external_id":{"pmid":["36599980"]},"oa":1}