Increasing the efficiency and targeting range of cytidine base editors through fusion of a single-stranded DNA-binding protein domain
Cytidine base editors are powerful genetic tools that catalyse cytidine to thymidine conversion at specific genomic loci, and further improvement of the editing range and efficiency is critical for their broader applications. Through insertion of a non-sequence-specific single-stranded DNA-binding d...
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| Veröffentlicht in: | Nature cell biology 2020-06, Vol.22 (6), p.740-750 |
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| creator | Zhang, Xiaohui Chen, Liang Zhu, Biyun Wang, Liren Chen, Caiyu Hong, Mengjia Huang, Yifan Li, Huiying Han, Honghui Cai, Bailian Yu, Weishi Yin, Shuming Yang, Lei Yang, Zuozhen Liu, Meizhen Zhang, Ying Mao, Zhiyong Wu, Yuxuan Liu, Mingyao Li, Dali |
| description | Cytidine base editors are powerful genetic tools that catalyse cytidine to thymidine conversion at specific genomic loci, and further improvement of the editing range and efficiency is critical for their broader applications. Through insertion of a non-sequence-specific single-stranded DNA-binding domain from Rad51 protein between Cas9 nickase and the deaminases, serial hyper cytidine base editors were generated with substantially increased activity and an expanded editing window towards the protospacer adjacent motif in both cell lines and mouse embryos. Additionally, hyeA3A-BE4max selectively catalysed cytidine conversion in TC motifs with a broader editing range and much higher activity (up to 257-fold) compared with eA3A-BE4max. Moreover, hyeA3A-BE4max specifically generated a C-to-T conversion without inducing bystander mutations in the haemoglobin gamma gene promoter to mimic a naturally occurring genetic variant for amelioration of β-haemoglobinopathy, suggesting the therapeutic potential of the improved base editors.
Li and colleagues report base editor variants with improved targeting efficiencies and broader editing windows by fusing the original base editors with the single-stranded DNA-binding domain of Rad51. |
| doi_str_mv | 10.1038/s41556-020-0518-8 |
| format | Article |
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Li and colleagues report base editor variants with improved targeting efficiencies and broader editing windows by fusing the original base editors with the single-stranded DNA-binding domain of Rad51.</description><identifier>ISSN: 1465-7392</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/s41556-020-0518-8</identifier><identifier>PMID: 32393889</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/31 ; 14/34 ; 38/23 ; 38/44 ; 45/22 ; 45/41 ; 45/77 ; 631/136/1425 ; 631/1647/1511 ; 631/337/1427 ; 64/60 ; AC generators ; Animals ; Binding proteins ; Biomedical and Life Sciences ; Cancer Research ; Cell Biology ; Cell Differentiation ; Cell lines ; Comparative analysis ; Conversion ; CRISPR-Cas Systems ; Cytidine - chemistry ; Cytidine - genetics ; Deoxyribonucleic acid ; Developmental Biology ; DNA ; DNA-binding protein ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Editing ; Editors ; Embryo, Mammalian - cytology ; Embryo, Mammalian - metabolism ; Embryos ; Female ; Gene Editing ; Genetic diversity ; Genetic variance ; HEK293 Cells ; Hemoglobin ; Humans ; Insertion ; Life Sciences ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Mutation ; Nucleotide sequence ; Protein binding ; Protein Domains ; Proteins ; Rad51 protein ; Rad51 Recombinase - genetics ; Rad51 Recombinase - metabolism ; Single-stranded DNA ; Single-stranded DNA-binding protein ; Stem Cells ; technical-report ; Thymidine</subject><ispartof>Nature cell biology, 2020-06, Vol.22 (6), p.740-750</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-87b72451e34497be751d87e5c1fb33e070bd386286c94ed7180651791742028e3</citedby><cites>FETCH-LOGICAL-c473t-87b72451e34497be751d87e5c1fb33e070bd386286c94ed7180651791742028e3</cites><orcidid>0000-0002-0046-8493 ; 0000-0001-5832-7186 ; 0000-0002-5298-1918</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41556-020-0518-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41556-020-0518-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32393889$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Xiaohui</creatorcontrib><creatorcontrib>Chen, Liang</creatorcontrib><creatorcontrib>Zhu, Biyun</creatorcontrib><creatorcontrib>Wang, Liren</creatorcontrib><creatorcontrib>Chen, Caiyu</creatorcontrib><creatorcontrib>Hong, Mengjia</creatorcontrib><creatorcontrib>Huang, Yifan</creatorcontrib><creatorcontrib>Li, Huiying</creatorcontrib><creatorcontrib>Han, Honghui</creatorcontrib><creatorcontrib>Cai, Bailian</creatorcontrib><creatorcontrib>Yu, Weishi</creatorcontrib><creatorcontrib>Yin, Shuming</creatorcontrib><creatorcontrib>Yang, Lei</creatorcontrib><creatorcontrib>Yang, Zuozhen</creatorcontrib><creatorcontrib>Liu, Meizhen</creatorcontrib><creatorcontrib>Zhang, Ying</creatorcontrib><creatorcontrib>Mao, Zhiyong</creatorcontrib><creatorcontrib>Wu, Yuxuan</creatorcontrib><creatorcontrib>Liu, Mingyao</creatorcontrib><creatorcontrib>Li, Dali</creatorcontrib><title>Increasing the efficiency and targeting range of cytidine base editors through fusion of a single-stranded DNA-binding protein domain</title><title>Nature cell biology</title><addtitle>Nat Cell Biol</addtitle><addtitle>Nat Cell Biol</addtitle><description>Cytidine base editors are powerful genetic tools that catalyse cytidine to thymidine conversion at specific genomic loci, and further improvement of the editing range and efficiency is critical for their broader applications. Through insertion of a non-sequence-specific single-stranded DNA-binding domain from Rad51 protein between Cas9 nickase and the deaminases, serial hyper cytidine base editors were generated with substantially increased activity and an expanded editing window towards the protospacer adjacent motif in both cell lines and mouse embryos. Additionally, hyeA3A-BE4max selectively catalysed cytidine conversion in TC motifs with a broader editing range and much higher activity (up to 257-fold) compared with eA3A-BE4max. Moreover, hyeA3A-BE4max specifically generated a C-to-T conversion without inducing bystander mutations in the haemoglobin gamma gene promoter to mimic a naturally occurring genetic variant for amelioration of β-haemoglobinopathy, suggesting the therapeutic potential of the improved base editors.
Li and colleagues report base editor variants with improved targeting efficiencies and broader editing windows by fusing the original base editors with the single-stranded DNA-binding domain of Rad51.</description><subject>13/1</subject><subject>13/31</subject><subject>14/34</subject><subject>38/23</subject><subject>38/44</subject><subject>45/22</subject><subject>45/41</subject><subject>45/77</subject><subject>631/136/1425</subject><subject>631/1647/1511</subject><subject>631/337/1427</subject><subject>64/60</subject><subject>AC generators</subject><subject>Animals</subject><subject>Binding proteins</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Cell Differentiation</subject><subject>Cell lines</subject><subject>Comparative analysis</subject><subject>Conversion</subject><subject>CRISPR-Cas Systems</subject><subject>Cytidine - chemistry</subject><subject>Cytidine - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>Developmental Biology</subject><subject>DNA</subject><subject>DNA-binding protein</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Editing</subject><subject>Editors</subject><subject>Embryo, Mammalian - cytology</subject><subject>Embryo, Mammalian - metabolism</subject><subject>Embryos</subject><subject>Female</subject><subject>Gene Editing</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>HEK293 Cells</subject><subject>Hemoglobin</subject><subject>Humans</subject><subject>Insertion</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred ICR</subject><subject>Mutation</subject><subject>Nucleotide sequence</subject><subject>Protein binding</subject><subject>Protein Domains</subject><subject>Proteins</subject><subject>Rad51 protein</subject><subject>Rad51 Recombinase - genetics</subject><subject>Rad51 Recombinase - metabolism</subject><subject>Single-stranded DNA</subject><subject>Single-stranded DNA-binding protein</subject><subject>Stem 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the efficiency and targeting range of cytidine base editors through fusion of a single-stranded DNA-binding protein domain</title><author>Zhang, Xiaohui ; Chen, Liang ; Zhu, Biyun ; Wang, Liren ; Chen, Caiyu ; Hong, Mengjia ; Huang, Yifan ; Li, Huiying ; Han, Honghui ; Cai, Bailian ; Yu, Weishi ; Yin, Shuming ; Yang, Lei ; Yang, Zuozhen ; Liu, Meizhen ; Zhang, Ying ; Mao, Zhiyong ; Wu, Yuxuan ; Liu, Mingyao ; Li, Dali</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-87b72451e34497be751d87e5c1fb33e070bd386286c94ed7180651791742028e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/1</topic><topic>13/31</topic><topic>14/34</topic><topic>38/23</topic><topic>38/44</topic><topic>45/22</topic><topic>45/41</topic><topic>45/77</topic><topic>631/136/1425</topic><topic>631/1647/1511</topic><topic>631/337/1427</topic><topic>64/60</topic><topic>AC 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Through insertion of a non-sequence-specific single-stranded DNA-binding domain from Rad51 protein between Cas9 nickase and the deaminases, serial hyper cytidine base editors were generated with substantially increased activity and an expanded editing window towards the protospacer adjacent motif in both cell lines and mouse embryos. Additionally, hyeA3A-BE4max selectively catalysed cytidine conversion in TC motifs with a broader editing range and much higher activity (up to 257-fold) compared with eA3A-BE4max. Moreover, hyeA3A-BE4max specifically generated a C-to-T conversion without inducing bystander mutations in the haemoglobin gamma gene promoter to mimic a naturally occurring genetic variant for amelioration of β-haemoglobinopathy, suggesting the therapeutic potential of the improved base editors.
Li and colleagues report base editor variants with improved targeting efficiencies and broader editing windows by fusing the original base editors with the single-stranded DNA-binding domain of Rad51.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32393889</pmid><doi>10.1038/s41556-020-0518-8</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-0046-8493</orcidid><orcidid>https://orcid.org/0000-0001-5832-7186</orcidid><orcidid>https://orcid.org/0000-0002-5298-1918</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-7392 |
| ispartof | Nature cell biology, 2020-06, Vol.22 (6), p.740-750 |
| issn | 1465-7392 1476-4679 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2401805459 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 13/1 13/31 14/34 38/23 38/44 45/22 45/41 45/77 631/136/1425 631/1647/1511 631/337/1427 64/60 AC generators Animals Binding proteins Biomedical and Life Sciences Cancer Research Cell Biology Cell Differentiation Cell lines Comparative analysis Conversion CRISPR-Cas Systems Cytidine - chemistry Cytidine - genetics Deoxyribonucleic acid Developmental Biology DNA DNA-binding protein DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Editing Editors Embryo, Mammalian - cytology Embryo, Mammalian - metabolism Embryos Female Gene Editing Genetic diversity Genetic variance HEK293 Cells Hemoglobin Humans Insertion Life Sciences Mice Mice, Inbred C57BL Mice, Inbred ICR Mutation Nucleotide sequence Protein binding Protein Domains Proteins Rad51 protein Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Single-stranded DNA Single-stranded DNA-binding protein Stem Cells technical-report Thymidine |
| title | Increasing the efficiency and targeting range of cytidine base editors through fusion of a single-stranded DNA-binding protein domain |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T13%3A51%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Increasing%20the%20efficiency%20and%20targeting%20range%20of%20cytidine%20base%20editors%20through%20fusion%20of%20a%20single-stranded%20DNA-binding%20protein%20domain&rft.jtitle=Nature%20cell%20biology&rft.au=Zhang,%20Xiaohui&rft.date=2020-06-01&rft.volume=22&rft.issue=6&rft.spage=740&rft.epage=750&rft.pages=740-750&rft.issn=1465-7392&rft.eissn=1476-4679&rft_id=info:doi/10.1038/s41556-020-0518-8&rft_dat=%3Cgale_proqu%3EA626151704%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2410659026&rft_id=info:pmid/32393889&rft_galeid=A626151704&rfr_iscdi=true |