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Cytosine base editors with minimized unguided DNA and RNA off-target events and high on-target activity

Author

Listed:
  • Yi Yu

    (Beam Therapeutics)

  • Thomas C. Leete

    (Beam Therapeutics)

  • David A. Born

    (Beam Therapeutics)

  • Lauren Young

    (Beam Therapeutics)

  • Luis A. Barrera

    (Beam Therapeutics)

  • Seung-Joo Lee

    (Beam Therapeutics)

  • Holly A. Rees

    (Beam Therapeutics)

  • Giuseppe Ciaramella

    (Beam Therapeutics)

  • Nicole M. Gaudelli

    (Beam Therapeutics)

Abstract

Cytosine base editors (CBEs) enable efficient, programmable reversion of T•A to C•G point mutations in the human genome. Recently, cytosine base editors with rAPOBEC1 were reported to induce unguided cytosine deamination in genomic DNA and cellular RNA. Here we report eight next-generation CBEs (BE4 with either RrA3F [wt, F130L], AmAPOBEC1, SsAPOBEC3B [wt, R54Q], or PpAPOBEC1 [wt, H122A, R33A]) that display comparable DNA on-target editing frequencies, whilst eliciting a 12- to 69-fold reduction in C-to-U edits in the transcriptome, and up to a 45-fold overall reduction in unguided off-target DNA deamination relative to BE4 containing rAPOBEC1. Further, no enrichment of genome-wide C•G to T•A edits are observed in mammalian cells following transfection of mRNA encoding five of these next-generation editors. Taken together, these next-generation CBEs represent a collection of base editing tools for applications in which minimized off-target and high on-target activity are required.

Suggested Citation

  • Yi Yu & Thomas C. Leete & David A. Born & Lauren Young & Luis A. Barrera & Seung-Joo Lee & Holly A. Rees & Giuseppe Ciaramella & Nicole M. Gaudelli, 2020. "Cytosine base editors with minimized unguided DNA and RNA off-target events and high on-target activity," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15887-5
    DOI: 10.1038/s41467-020-15887-5
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    Cited by:

    1. Ang Li & Hitoshi Mitsunobu & Shin Yoshioka & Takahisa Suzuki & Akihiko Kondo & Keiji Nishida, 2022. "Cytosine base editing systems with minimized off-target effect and molecular size," Nature Communications, Nature, vol. 13(1), pages 1-8, December.

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