IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45100-w.html
   My bibliography  Save this article

Compact zinc finger architecture utilizing toxin-derived cytidine deaminases for highly efficient base editing in human cells

Author

Listed:
  • Friedrich Fauser

    (Sangamo Therapeutics, Inc.)

  • Bhakti N. Kadam

    (Sangamo Therapeutics, Inc.)

  • Sebastian Arangundy-Franklin

    (Sangamo Therapeutics, Inc.)

  • Jessica E. Davis

    (Sangamo Therapeutics, Inc.)

  • Vishvesha Vaidya

    (Sangamo Therapeutics, Inc.)

  • Nicola J. Schmidt

    (Sangamo Therapeutics, Inc.)

  • Garrett Lew

    (Sangamo Therapeutics, Inc.)

  • Danny F. Xia

    (Sangamo Therapeutics, Inc.)

  • Rakshaa Mureli

    (Sangamo Therapeutics, Inc.)

  • Colman Ng

    (Sangamo Therapeutics, Inc.)

  • Yuanyue Zhou

    (Sangamo Therapeutics, Inc.)

  • Nicholas A. Scarlott

    (Sangamo Therapeutics, Inc.)

  • Jason Eshleman

    (Sangamo Therapeutics, Inc.)

  • Yuri R. Bendaña

    (Sangamo Therapeutics, Inc.)

  • David A. Shivak

    (Sangamo Therapeutics, Inc.)

  • Andreas Reik

    (Sangamo Therapeutics, Inc.)

  • Patrick Li

    (Sangamo Therapeutics, Inc.)

  • Gregory D. Davis

    (Sangamo Therapeutics, Inc.)

  • Jeffrey C. Miller

    (Sangamo Therapeutics, Inc.)

Abstract

Nucleobase editors represent an emerging technology that enables precise single-base edits to the genomes of eukaryotic cells. Most nucleobase editors use deaminase domains that act upon single-stranded DNA and require RNA-guided proteins such as Cas9 to unwind the DNA prior to editing. However, the most recent class of base editors utilizes a deaminase domain, DddAtox, that can act upon double-stranded DNA. Here, we target DddAtox fragments and a FokI-based nickase to the human CIITA gene by fusing these domains to arrays of engineered zinc fingers (ZFs). We also identify a broad variety of Toxin-Derived Deaminases (TDDs) orthologous to DddAtox that allow us to fine-tune properties such as targeting density and specificity. TDD-derived ZF base editors enable up to 73% base editing in T cells with good cell viability and favorable specificity.

Suggested Citation

  • Friedrich Fauser & Bhakti N. Kadam & Sebastian Arangundy-Franklin & Jessica E. Davis & Vishvesha Vaidya & Nicola J. Schmidt & Garrett Lew & Danny F. Xia & Rakshaa Mureli & Colman Ng & Yuanyue Zhou & N, 2024. "Compact zinc finger architecture utilizing toxin-derived cytidine deaminases for highly efficient base editing in human cells," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45100-w
    DOI: 10.1038/s41467-024-45100-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45100-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-45100-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Hyunji Lee & Seonghyun Lee & Gayoung Baek & Annie Kim & Beum-Chang Kang & Huiyun Seo & Jin-Soo Kim, 2021. "Mitochondrial DNA editing in mice with DddA-TALE fusion deaminases," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
    2. Luhan Yang & Adrian W. Briggs & Wei Leong Chew & Prashant Mali & Marc Guell & John Aach & Daniel Bryan Goodman & David Cox & Yinan Kan & Emal Lesha & Venkataramanan Soundararajan & Feng Zhang & George, 2016. "Engineering and optimising deaminase fusions for genome editing," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    3. Li Mi & Ming Shi & Yu-Xuan Li & Gang Xie & Xichen Rao & Damu Wu & Aimin Cheng & Mengxiao Niu & Fengli Xu & Ying Yu & Ning Gao & Wensheng Wei & Xianhua Wang & Yangming Wang, 2023. "DddA homolog search and engineering expand sequence compatibility of mitochondrial base editing," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    4. Joseph Kreitz & Mirco J. Friedrich & Akash Guru & Blake Lash & Makoto Saito & Rhiannon K. Macrae & Feng Zhang, 2023. "Programmable protein delivery with a bacterial contractile injection system," Nature, Nature, vol. 616(7956), pages 357-364, April.
    5. Pedro Silva-Pinheiro & Pavel A. Nash & Lindsey Van Haute & Christian D. Mutti & Keira Turner & Michal Minczuk, 2022. "In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    6. Kayeong Lim & Sung-Ik Cho & Jin-Soo Kim, 2022. "Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    7. Zhixin Lei & Haowei Meng & Lulu Liu & Huanan Zhao & Xichen Rao & Yongchang Yan & Hao Wu & Min Liu & Aibin He & Chengqi Yi, 2022. "Mitochondrial base editor induces substantial nuclear off-target mutations," Nature, Nature, vol. 606(7915), pages 804-811, June.
    8. Young Geun Mok & Ji Min Lee & Eugene Chung & Jaesuk Lee & Kayeong Lim & Sung-Ik Cho & Jin-Soo Kim, 2022. "Base editing in human cells with monomeric DddA-TALE fusion deaminases," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    9. Beverly Y. Mok & Marcos H. de Moraes & Jun Zeng & Dustin E. Bosch & Anna V. Kotrys & Aditya Raguram & FoSheng Hsu & Matthew C. Radey & S. Brook Peterson & Vamsi K. Mootha & Joseph D. Mougous & David R, 2020. "A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing," Nature, Nature, vol. 583(7817), pages 631-637, July.
    10. Andrew V. Anzalone & Peyton B. Randolph & Jessie R. Davis & Alexander A. Sousa & Luke W. Koblan & Jonathan M. Levy & Peter J. Chen & Christopher Wilson & Gregory A. Newby & Aditya Raguram & David R. L, 2019. "Search-and-replace genome editing without double-strand breaks or donor DNA," Nature, Nature, vol. 576(7785), pages 149-157, December.
    11. Alexis C. Komor & Yongjoo B. Kim & Michael S. Packer & John A. Zuris & David R. Liu, 2016. "Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage," Nature, Nature, vol. 533(7603), pages 420-424, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Haifeng Sun & Zhaojun Wang & Limini Shen & Yeling Feng & Lu Han & Xuezhen Qian & Runde Meng & Kangming Ji & Dong Liang & Fei Zhou & Xin Lou & Jun Zhang & Bin Shen, 2023. "Developing mitochondrial base editors with diverse context compatibility and high fidelity via saturated spacer library," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Huawei Tong & Haoqiang Wang & Xuchen Wang & Nana Liu & Guoling Li & Danni Wu & Yun Li & Ming Jin & Hengbin Li & Yinghui Wei & Tong Li & Yuan Yuan & Linyu Shi & Xuan Yao & Yingsi Zhou & Hui Yang, 2024. "Development of deaminase-free T-to-S base editor and C-to-G base editor by engineered human uracil DNA glycosylase," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Young Geun Mok & Ji Min Lee & Eugene Chung & Jaesuk Lee & Kayeong Lim & Sung-Ik Cho & Jin-Soo Kim, 2022. "Base editing in human cells with monomeric DddA-TALE fusion deaminases," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Julian C. W. Willis & Pedro Silva-Pinheiro & Lily Widdup & Michal Minczuk & David R. Liu, 2022. "Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Emily Zhang & Monica E. Neugebauer & Nicholas A. Krasnow & David R. Liu, 2024. "Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Yuting Chen & Eriona Hysolli & Anlu Chen & Stephen Casper & Songlei Liu & Kevin Yang & Chenli Liu & George Church, 2022. "Multiplex base editing to convert TAG into TAA codons in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Jianli Tao & Daniel E. Bauer & Roberto Chiarle, 2023. "Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Xiaoguang Pan & Kunli Qu & Hao Yuan & Xi Xiang & Christian Anthon & Liubov Pashkova & Xue Liang & Peng Han & Giulia I. Corsi & Fengping Xu & Ping Liu & Jiayan Zhong & Yan Zhou & Tao Ma & Hui Jiang & J, 2022. "Massively targeted evaluation of therapeutic CRISPR off-targets in cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Guiquan Zhang & Yao Liu & Shisheng Huang & Shiyuan Qu & Daolin Cheng & Yuan Yao & Quanjiang Ji & Xiaolong Wang & Xingxu Huang & Jianghuai Liu, 2022. "Enhancement of prime editing via xrRNA motif-joined pegRNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Ronghao Chen & Yu Cao & Yajing Liu & Dongdong Zhao & Ju Li & Zhihui Cheng & Changhao Bi & Xueli Zhang, 2023. "Enhancement of a prime editing system via optimal recruitment of the pioneer transcription factor P65," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    11. Qichen Yuan & Xue Gao, 2022. "Multiplex base- and prime-editing with drive-and-process CRISPR arrays," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    12. Kun Jia & Yan-ru Cui & Shisheng Huang & Peihong Yu & Zhengxing Lian & Peixiang Ma & Jia Liu, 2022. "Phage peptides mediate precision base editing with focused targeting window," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    13. Xiangfeng Kong & Hainan Zhang & Guoling Li & Zikang Wang & Xuqiang Kong & Lecong Wang & Mingxing Xue & Weihong Zhang & Yao Wang & Jiajia Lin & Jingxing Zhou & Xiaowen Shen & Yinghui Wei & Na Zhong & W, 2023. "Engineered CRISPR-OsCas12f1 and RhCas12f1 with robust activities and expanded target range for genome editing," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    14. Péter István Kulcsár & András Tálas & Zoltán Ligeti & Sarah Laura Krausz & Ervin Welker, 2022. "SuperFi-Cas9 exhibits remarkable fidelity but severely reduced activity yet works effectively with ABE8e," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    15. You-Jeong Kim & Dayoung Yun & Jungjoon K. Lee & Cheulhee Jung & Aram J. Chung, 2024. "Highly efficient CRISPR-mediated genome editing through microfluidic droplet cell mechanoporation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    16. Yi-Li Feng & Qian Liu & Ruo-Dan Chen & Si-Cheng Liu & Zhi-Cheng Huang & Kun-Ming Liu & Xiao-Ying Yang & An-Yong Xie, 2022. "DNA nicks induce mutational signatures associated with BRCA1 deficiency," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Michael Kosicki & Felicity Allen & Frances Steward & Kärt Tomberg & Yangyang Pan & Allan Bradley, 2022. "Cas9-induced large deletions and small indels are controlled in a convergent fashion," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    18. Peter N. Ciaccia & Zhuobin Liang & Anabel Y. Schweitzer & Eli Metzner & Farren J. Isaacs, 2024. "Enhanced eMAGE applied to identify genetic factors of nuclear hormone receptor dysfunction via combinatorial gene editing," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    19. Marion Rosello & Malo Serafini & Luca Mignani & Dario Finazzi & Carine Giovannangeli & Marina C. Mione & Jean-Paul Concordet & Filippo Del Bene, 2022. "Disease modeling by efficient genome editing using a near PAM-less base editor in vivo," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    20. Ason C. Y. Chiang & Jan Ježek & Peiqiang Mu & Ying Di & Anna Klucnika & Martin Jabůrek & Petr Ježek & Hansong Ma, 2024. "Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45100-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.