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Orthogonal Cas9–Cas9 chimeras provide a versatile platform for genome editing

Author

Listed:
  • Mehmet Fatih Bolukbasi

    (University of Massachusetts Medical School
    University of Massachusetts Medical School
    Exonics Therapeutics)

  • Pengpeng Liu

    (University of Massachusetts Medical School)

  • Kevin Luk

    (University of Massachusetts Medical School)

  • Samantha F. Kwok

    (University of Massachusetts Medical School)

  • Ankit Gupta

    (University of Massachusetts Medical School
    Bluebird Bio.)

  • Nadia Amrani

    (University of Massachusetts Medical School)

  • Erik J. Sontheimer

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Lihua Julie Zhu

    (University of Massachusetts Medical School
    University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Scot A. Wolfe

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

Abstract

The development of robust, versatile and accurate toolsets is critical to facilitate therapeutic genome editing applications. Here we establish RNA-programmable Cas9-Cas9 chimeras, in single- and dual-nuclease formats, as versatile genome engineering systems. In both of these formats, Cas9-Cas9 fusions display an expanded targeting repertoire and achieve highly specific genome editing. Dual-nuclease Cas9-Cas9 chimeras have distinct advantages over monomeric Cas9s including higher target site activity and the generation of predictable precise deletion products between their target sites. At a therapeutically relevant site within the BCL11A erythroid enhancer, Cas9-Cas9 nucleases produced precise deletions that comprised up to 97% of all sequence alterations. Thus Cas9-Cas9 chimeras represent an important tool that could be particularly valuable for therapeutic genome editing applications where a precise cleavage position and defined sequence end products are desirable.

Suggested Citation

  • Mehmet Fatih Bolukbasi & Pengpeng Liu & Kevin Luk & Samantha F. Kwok & Ankit Gupta & Nadia Amrani & Erik J. Sontheimer & Lihua Julie Zhu & Scot A. Wolfe, 2018. "Orthogonal Cas9–Cas9 chimeras provide a versatile platform for genome editing," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07310-x
    DOI: 10.1038/s41467-018-07310-x
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    Cited by:

    1. Raed Ibraheim & Phillip W. L. Tai & Aamir Mir & Nida Javeed & Jiaming Wang & Tomás C. Rodríguez & Suk Namkung & Samantha Nelson & Eraj Shafiq Khokhar & Esther Mintzer & Stacy Maitland & Zexiang Chen &, 2021. "Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

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