Efficient precise knockin with a double cut HDR donor after CRISPR/Cas9-mediated double-stranded DNA cleavage View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-02-20

AUTHORS

Jian-Ping Zhang, Xiao-Lan Li, Guo-Hua Li, Wanqiu Chen, Cameron Arakaki, Gary D. Botimer, David Baylink, Lu Zhang, Wei Wen, Ya-Wen Fu, Jing Xu, Noah Chun, Weiping Yuan, Tao Cheng, Xiao-Bing Zhang

ABSTRACT

BackgroundPrecise genome editing via homology-directed repair (HDR) after double-stranded DNA (dsDNA) cleavage facilitates functional genomic research and holds promise for gene therapy. However, HDR efficiency remains low in some cell types, including some of great research and clinical interest, such as human induced pluripotent stem cells (iPSCs).ResultsHere, we show that a double cut HDR donor, which is flanked by single guide RNA (sgRNA)-PAM sequences and is released after CRISPR/Cas9 cleavage, increases HDR efficiency by twofold to fivefold relative to circular plasmid donors at one genomic locus in 293 T cells and two distinct genomic loci in iPSCs. We find that a 600 bp homology in both arms leads to high-level genome knockin, with 97–100% of the donor insertion events being mediated by HDR. The combined use of CCND1, a cyclin that functions in G1/S transition, and nocodazole, a G2/M phase synchronizer, doubles HDR efficiency to up to 30% in iPSCs.ConclusionsTaken together, these findings provide guidance for the design of HDR donor vectors and the selection of HDR-enhancing factors for applications in genome research and precision medicine. More... »

PAGES

35

References to SciGraph publications

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  • Journal

    TITLE

    Genome Biology

    ISSUE

    1

    VOLUME

    18

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13059-017-1164-8

    DOI

    http://dx.doi.org/10.1186/s13059-017-1164-8

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1083851310

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28219395


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