CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies
Inactivating p53 mutations are the most abundant genetic alterations found in cancer. Here we show that CRISPR/Cas9-induced double-stranded DNA breaks enrich for cells deficient in p53 and in genes of a core CRISPR-p53 tumor suppressor interactome. Such enrichment could predispose to cancer developm...
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sg-ntu-dr.10356-1635612023-02-28T20:02:24Z CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies Jiang, Long Ingelshed, Katrine Shen, Yunbing Boddul, Sanjaykumar V. Iyer, Vaishnavi Srinivasan Kasza, Zsolt Sedimbi, Saikiran Lane, David P. Wermeling, Fredrik School of Physical and Mathematical Sciences Science::Medicine Gene-Therapy Cancer Inactivating p53 mutations are the most abundant genetic alterations found in cancer. Here we show that CRISPR/Cas9-induced double-stranded DNA breaks enrich for cells deficient in p53 and in genes of a core CRISPR-p53 tumor suppressor interactome. Such enrichment could predispose to cancer development and thus pose a challenge for clinical CRISPR use. Transient p53 inhibition could suppress the enrichment of cells with these mutations. The level of DNA damage response induced by an sgRNA influenced the enrichment of p53-deficient cells and could be a relevant parameter in sgRNA design to limit cellular enrichment. Furthermore, a dataset of >800 human cancer cell lines identified additional factors influencing the enrichment of p53-mutated cells, including strong baseline CDKN1A expression as a predictor for an active CRISPR-p53 axis. Taken together, these data provide details about p53 biology in the context of CRISPR-induced DNA damage and identify strategies to enable safer CRISPR use. SIGNIFICANCE: CRISPR-mediated DNA damage enriches for cells with escape mutations in a core CRISPR-p53 interactome, which can be suppressed by transient inhibition of p53. Published version The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for AdvancedComputational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. This research was partly funded by grants from the Swedish Research Council (to F. Wermeling and D.P. Lane) , the Swedish Cancer Society, Karolinska Institutet and Magnus Bergvalls stiftelse (to F. Wermeling) , the China Scholarship Council (to L. Jiang and Y. Shen) , and the Nanyang Technological University-Karolinska Institutet Joint PhD Program (to V.S. Iyer). 2022-12-09T03:58:56Z 2022-12-09T03:58:56Z 2022 Journal Article Jiang, L., Ingelshed, K., Shen, Y., Boddul, S. V., Iyer, V. S., Kasza, Z., Sedimbi, S., Lane, D. P. & Wermeling, F. (2022). CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies. Cancer Research, 82(1), 36-45. https://dx.doi.org/10.1158/0008-5472.CAN-21-1692 0008-5472 https://hdl.handle.net/10356/163561 10.1158/0008-5472.CAN-21-1692 34750099 2-s2.0-85122372149 1 82 36 45 en Cancer Research © 2021 The Authors. Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. application/pdf |
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Science::Medicine Gene-Therapy Cancer Jiang, Long Ingelshed, Katrine Shen, Yunbing Boddul, Sanjaykumar V. Iyer, Vaishnavi Srinivasan Kasza, Zsolt Sedimbi, Saikiran Lane, David P. Wermeling, Fredrik CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies |
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Inactivating p53 mutations are the most abundant genetic alterations found in cancer. Here we show that CRISPR/Cas9-induced double-stranded DNA breaks enrich for cells deficient in p53 and in genes of a core CRISPR-p53 tumor suppressor interactome. Such enrichment could predispose to cancer development and thus pose a challenge for clinical CRISPR use. Transient p53 inhibition could suppress the enrichment of cells with these mutations. The level of DNA damage response induced by an sgRNA influenced the enrichment of p53-deficient cells and could be a relevant parameter in sgRNA design to limit cellular enrichment. Furthermore, a dataset of >800 human cancer cell lines identified additional factors influencing the enrichment of p53-mutated cells, including strong baseline CDKN1A expression as a predictor for an active CRISPR-p53 axis. Taken together, these data provide details about p53 biology in the context of CRISPR-induced DNA damage and identify strategies to enable safer CRISPR use.
SIGNIFICANCE: CRISPR-mediated DNA damage enriches for cells with escape mutations in a core CRISPR-p53 interactome, which can be suppressed by transient inhibition of p53. |
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School of Physical and Mathematical Sciences |
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School of Physical and Mathematical Sciences Jiang, Long Ingelshed, Katrine Shen, Yunbing Boddul, Sanjaykumar V. Iyer, Vaishnavi Srinivasan Kasza, Zsolt Sedimbi, Saikiran Lane, David P. Wermeling, Fredrik |
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Article |
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Jiang, Long Ingelshed, Katrine Shen, Yunbing Boddul, Sanjaykumar V. Iyer, Vaishnavi Srinivasan Kasza, Zsolt Sedimbi, Saikiran Lane, David P. Wermeling, Fredrik |
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Jiang, Long |
title |
CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies |
title_short |
CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies |
title_full |
CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies |
title_fullStr |
CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies |
title_full_unstemmed |
CRISPR/Cas9-induced DNA damage enriches for mutations in a p53-linked interactome: implications for CRISPR-based therapies |
title_sort |
crispr/cas9-induced dna damage enriches for mutations in a p53-linked interactome: implications for crispr-based therapies |
publishDate |
2022 |
url |
https://hdl.handle.net/10356/163561 |
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1759853936278241280 |