CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response (original) (raw)
- Brief Communication
- Published: 11 June 2018
- Sandeep Botla1 na1,
- Jenna Persson ORCID: orcid.org/0000-0002-0208-80801,
- Bernhard Schmierer1 na2 &
- …
- Jussi Taipale1,2,3 na2
Nature Medicine volume 24, pages 927–930 (2018)Cite this article
- 61k Accesses
- 815 Citations
- 1648 Altmetric
- Metrics details
Subjects
Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Hustedt, N. & Durocher, D. Nat. Cell Biol. 19, 1–9 (2016).
Article PubMed CAS Google Scholar - Hohmann, S. & Gozalbo, D. Mol. Gen. Genet. 211, 446–454 (1988).
Article PubMed CAS Google Scholar - Richardson, C. D., Ray, G. J., DeWitt, M. A., Curie, G. L. & Corn, J. E. Nat. Biotechnol. 34, 339–344 (2016).
Article PubMed CAS Google Scholar - DeWitt, M. A. et al. Sci. Transl. Med. 8, 360ra134 (2016).
Article PubMed PubMed Central CAS Google Scholar - Yin, H. et al. Nat. Biotechnol. 32, 551–553 (2014).
Article PubMed PubMed Central CAS Google Scholar - Dever, D. P. et al. Nature 539, 384–389 (2016).
Article PubMed PubMed Central CAS Google Scholar - Lee, K. et al. eLife 6, e25312 (2017).
- Maruyama, T. et al. Nat. Biotechnol. 33, 538–542 (2015).
Article PubMed PubMed Central CAS Google Scholar - Schmierer, B. et al. Mol. Syst. Biol. 13, 945 (2017).
Article PubMed PubMed Central Google Scholar - Luo, M. & Chen, Y. Int. J. Ophthalmol. 11, 150–159 (2018).
PubMed PubMed Central Google Scholar - Otto, T. & Sicinski, P. Nat. Rev. Cancer 17, 93–115 (2017).
Article PubMed PubMed Central CAS Google Scholar - Sokolova, M. et al. Cell Cycle 16, 189–199 (2017).
Article PubMed CAS Google Scholar - Doench, J. G. et al. Nat. Biotechnol. 34, 184–191 (2016).
Article PubMed PubMed Central CAS Google Scholar - Wang, J., Vasaikar, S., Shi, Z., Greer, M. & Zhang, B. Nucleic Acids Res. 45, W130–W137 (2017).
Article PubMed PubMed Central CAS Google Scholar - Canny, M. D. et al. Nat. Biotechnol. 36, 95–102 (2018).
Article PubMed CAS Google Scholar - Cuella-Martin, R. et al. Mol. Cell 64, 51–64 (2016).
Article PubMed PubMed Central CAS Google Scholar - Muerdter, F. et al. Nat. Methods 15, 141–149 (2018).
Article PubMed CAS Google Scholar - Li, W. et al. Genome Biol. 15, 554 (2014).
Article PubMed PubMed Central CAS Google Scholar - Wang, T. et al. Science 350, 1096–1101 (2015).
Article PubMed PubMed Central CAS Google Scholar - Tsai, S. Q. et al. Nat. Biotechnol. 33, 187–197 (2015).
Article PubMed CAS Google Scholar
Acknowledgements
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.
Author information
Author notes
- These authors contributed equally: Emma Haapaniemi, Sandeep Botla.
- These authors jointly supervised this work: Bernhard Schmierer, Jussi Taipale.
Authors and Affiliations
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
Emma Haapaniemi, Sandeep Botla, Jenna Persson, Bernhard Schmierer & Jussi Taipale - Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland
Emma Haapaniemi & Jussi Taipale - Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Jussi Taipale
Authors
- Emma Haapaniemi
You can also search for this author inPubMed Google Scholar - Sandeep Botla
You can also search for this author inPubMed Google Scholar - Bernhard Schmierer
You can also search for this author inPubMed Google Scholar - Jussi Taipale
You can also search for this author inPubMed Google Scholar
Contributions
E.H., B.S. and J.T. wrote the manuscript. S.B., B.S. and J.P. conducted the genome-wide knockout screens. E.H., B.S. and S.B. prepared the cell lines and performed the flow cytometry experiments. J.T. and B.S. supervised the study. All authors read and approved the final manuscript.
Corresponding authors
Correspondence toBernhard Schmierer or Jussi Taipale.
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
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
- Received: 11 September 2017
- Accepted: 23 April 2018
- Published: 11 June 2018
- Issue Date: July 2018
- DOI: https://doi.org/10.1038/s41591-018-0049-z