Enabling large-scale genome editing at repetitive elements by reducing DNA nicking

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• dc.contributor.author Smith, Cory J.
• dc.contributor.author Castanon, Oscar
• dc.contributor.author Said, Khaled
• dc.contributor.author Volf, Verena
• dc.contributor.author Khoshakhlagh, Parastoo
• dc.contributor.author Hornick, Amanda
• dc.contributor.author Ferreira, Raphael
• dc.contributor.author Wu, Chun-Ting
• dc.contributor.author Güell Cargol, Marc, 1982-
• dc.contributor.author Garg, Shilpa
• dc.contributor.author Ng, Alex H. M.
• dc.contributor.author Myllykallio, Hannu
• dc.contributor.author Church, George M.
• dc.date.accessioned 2020-06-04T06:23:29Z
• dc.date.available 2020-06-04T06:23:29Z
• dc.date.issued 2020
• dc.description.abstract To extend the frontier of genome editing and enable editing of repetitive elements of mammalian genomes, we made use of a set of dead-Cas9 base editor (dBE) variants that allow editing at tens of thousands of loci per cell by overcoming the cell death associated with DNA double-strand breaks and single-strand breaks. We used a set of gRNAs targeting repetitive elements-ranging in target copy number from about 32 to 161 000 per cell. dBEs enabled survival after large-scale base editing, allowing targeted mutations at up to ∼13 200 and ∼12 200 loci in 293T and human induced pluripotent stem cells (hiPSCs), respectively, three orders of magnitude greater than previously recorded. These dBEs can overcome current on-target mutation and toxicity barriers that prevent cell survival after large-scale genome engineering.
• dc.format.mimetype application/pdf
• dc.identifier.citation Smith CJ, Castanon O, Said K, Volf V, Khoshakhlagh P, Hornick A, Ferreira R, Wu CT, Güell M, Garg S, Ng AHM, Myllykallio H, Church GM. Enabling large-scale genome editing at repetitive elements by reducing DNA nicking. Nucleic Acids Res. 2020; 48(9):5183-95. DOI: 10.1093/nar/gkaa239
• dc.identifier.doi http://dx.doi.org/10.1093/nar/gkaa239
• dc.identifier.issn 0305-1048
• dc.identifier.uri http://hdl.handle.net/10230/44895
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Nucleic Acids Res. 2020; 48(9):5183-95
• dc.rights © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.title Enabling large-scale genome editing at repetitive elements by reducing DNA nicking
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion