Here, we report that genome editing by CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9.
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Part of this work was carried out at the High Throughput Genome Engineering Facility and the Swedish National Genomics Infrastructure funded by Science for Life Laboratory (Scilifelab). The Knut and Alice Wallenberg Foundation, Cancerfonden, Barncancerfonden and the Academy of Finland supported this work. We thank H. Han and Y. Bryceson for providing equipment, the Protein Science Facility at Karolinska Institutet, as well as I. Sur and T. Kivioja for their comments on the manuscript.
The authors declare no competing interests.
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Haapaniemi, E., Botla, S., Persson, J. et al. CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med 24, 927–930 (2018). https://doi.org/10.1038/s41591-018-0049-z
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