Cytosine base editing systems with minimized off-target effect and molecular size
Ang Li,
Hitoshi Mitsunobu,
Shin Yoshioka,
Takahisa Suzuki,
Akihiko Kondo and
Keiji Nishida (keiji_nishida@people.kobe-u.ac.jp)
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Ang Li: Kobe University
Hitoshi Mitsunobu: Kobe University
Shin Yoshioka: Kobe University
Takahisa Suzuki: Kobe University
Akihiko Kondo: Kobe University
Keiji Nishida: Kobe University
Nature Communications, 2022, vol. 13, issue 1, 1-8
Abstract:
Abstract Cytosine base editing enables the installation of specific point mutations without double-strand breaks in DNA and is advantageous for various applications such as gene therapy, but further reduction of off-target risk and development of efficient delivery methods are desired. Here we show structure-based rational engineering of the cytosine base editing system Target-AID to minimize its off-target effect and molecular size. By intensive and careful truncation, DNA-binding domain of its deaminase PmCDA1 is eliminated and additional mutations are introduced to restore enzyme function. The resulting tCDA1EQ is effective in N-terminal fusion (AID-2S) or inlaid architecture (AID-3S) with Cas9, showing minimized RNA-mediated editing and gRNA-dependent/independent DNA off-targets, as assessed in human cells. Combining with the smaller Cas9 ortholog system (SaCas9), a cytosine base editing system is created that is within the size limit of AAV vector.
Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32157-8
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DOI: 10.1038/s41467-022-32157-8
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