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Title: CRISPR-Cas3 induces broad and unidirectional genome editing in human cells
Authors: Hiroyuki Morisaka
Kazuto Yoshimi
Yuya Okuzaki
Peter Gee
Yayoi Kunihiro
Ekasit Sonpho
Huaigeng Xu
Noriko Sasakawa
Yuki Naito
Shinichiro Nakada
Takashi Yamamoto
Shigetoshi Sano
Akitsu Hotta
Junji Takeda
Tomoji Mashimo
Center for iPS Cell Research and Application
Institute of Medical Science The University of Tokyo
Hiroshima University
Osaka University
National Institute of Genetics Mishima
Kochi University
Mahidol University
Database Center for Life Science (DBCLS)
Keywords: Biochemistry, Genetics and Molecular Biology;Chemistry
Issue Date: 1-Dec-2019
Citation: Nature Communications. Vol.10, No.1 (2019)
Abstract: © 2019, The Author(s). Although single-component Class 2 CRISPR systems, such as type II Cas9 or type V Cas12a (Cpf1), are widely used for genome editing in eukaryotic cells, the application of multi-component Class 1 CRISPR has been less developed. Here we demonstrate that type I-E CRISPR mediates distinct DNA cleavage activity in human cells. Notably, Cas3, which possesses helicase and nuclease activity, predominantly triggered several thousand base pair deletions upstream of the 5′-ARG protospacer adjacent motif (PAM), without prominent off-target activity. This Cas3-mediated directional and broad DNA degradation can be used to introduce functional gene knockouts and knock-ins. As an example of potential therapeutic applications, we show Cas3-mediated exon-skipping of the Duchenne muscular dystrophy (DMD) gene in patient-induced pluripotent stem cells (iPSCs). These findings broaden our understanding of the Class 1 CRISPR system, which may serve as a unique genome editing tool in eukaryotic cells distinct from the Class 2 CRISPR system.
ISSN: 20411723
Appears in Collections:Scopus 2019

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