Inducing multiple nicks promotes interhomolog homologous recombination to correct heterozygous mutations in somatic cells

Akiko Tomita, Hiroyuki Sasanuma, Tomoo Owa, Yuka Nakazawa, Mayuko Shimada, Takahiro Fukuoka, Tomoo Ogi and Shinichiro Nakada ()
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Akiko Tomita: Osaka University, Suita
Hiroyuki Sasanuma: Tokyo Metropolitan Institute of Medical Science
Tomoo Owa: Osaka University, Suita
Yuka Nakazawa: Nagoya University
Mayuko Shimada: Nagoya University
Takahiro Fukuoka: Nagoya University
Tomoo Ogi: Nagoya University
Shinichiro Nakada: Osaka University, Suita

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract CRISPR/Cas9-mediated gene editing has great potential utility for treating genetic diseases. However, its therapeutic applications are limited by unintended genomic alterations arising from DNA double-strand breaks and random integration of exogenous DNA. In this study, we propose NICER, a method for correcting heterozygous mutations that employs multiple nicks (MNs) induced by Cas9 nickase and a homologous chromosome as an endogenous repair template. Although a single nick near the mutation site rarely leads to successful gene correction, additional nicks on homologous chromosomes strongly enhance gene correction efficiency via interhomolog homologous recombination (IH-HR). This process partially depends on BRCA1 and BRCA2, suggesting the existence of several distinct pathways for MN-induced IH-HR. According to a genomic analysis, NICER rarely induces unintended genomic alterations. Furthermore, NICER restores the expression of disease-causing genes in cells derived from genetic diseases with compound heterozygous mutations. Overall, NICER provides a precise strategy for gene correction.

Date: 2023
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DOI: 10.1038/s41467-023-41048-5

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