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Engineering and optimising deaminase fusions for genome editing

Author

Listed:
  • Luhan Yang

    (Harvard Medical School
    Program in Biological and Biomedical Sciences, Harvard Medical School
    eGenesis Inc.
    Present address: eGenesis Inc., 1 Kendall Square, Building 200, Cambridge Biolabs, Cambridge, Massachusetts 02139, USA)

  • Adrian W. Briggs

    (Harvard Medical School)

  • Wei Leong Chew

    (Harvard Medical School
    Program in Biological and Biomedical Sciences, Harvard Medical School
    Present address: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore)

  • Prashant Mali

    (Harvard Medical School)

  • Marc Guell

    (Harvard Medical School
    eGenesis Inc.
    Present address: eGenesis Inc., 1 Kendall Square, Building 200, Cambridge Biolabs, Cambridge, Massachusetts 02139, USA)

  • John Aach

    (Harvard Medical School)

  • Daniel Bryan Goodman

    (Harvard Medical School
    Harvard-MIT Division of Health Science and Technology)

  • David Cox

    (Harvard-MIT Division of Health Science and Technology)

  • Yinan Kan

    (Harvard Medical School
    eGenesis Inc.
    Present address: eGenesis Inc., 1 Kendall Square, Building 200, Cambridge Biolabs, Cambridge, Massachusetts 02139, USA)

  • Emal Lesha

    (Harvard Medical School
    eGenesis Inc.
    Present address: eGenesis Inc., 1 Kendall Square, Building 200, Cambridge Biolabs, Cambridge, Massachusetts 02139, USA)

  • Venkataramanan Soundararajan

    (Harvard Medical School)

  • Feng Zhang

    (Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, MIT
    MIT Cambridge)

  • George Church

    (Harvard Medical School
    Harvard-MIT Division of Health Science and Technology
    Wyss Institute for Biologically Inspired Engineering)

Abstract

Precise editing is essential for biomedical research and gene therapy. Yet, homology-directed genome modification is limited by the requirements for genomic lesions, homology donors and the endogenous DNA repair machinery. Here we engineered programmable cytidine deaminases and test if we could introduce site-specific cytidine to thymidine transitions in the absence of targeted genomic lesions. Our programmable deaminases effectively convert specific cytidines to thymidines with 13% efficiency in Escherichia coli and 2.5% in human cells. However, off-target deaminations were detected more than 150 bp away from the target site. Moreover, whole genome sequencing revealed that edited bacterial cells did not harbour chromosomal abnormalities but demonstrated elevated global cytidine deamination at deaminase intrinsic binding sites. Therefore programmable deaminases represent a promising genome editing tool in prokaryotes and eukaryotes. Future engineering is required to overcome the processivity and the intrinsic DNA binding affinity of deaminases for safer therapeutic applications.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13330
    DOI: 10.1038/ncomms13330
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    Cited by:

    1. 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.
    2. 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.

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