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Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens
Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704667/ https://www.ncbi.nlm.nih.gov/pubmed/33257658 http://dx.doi.org/10.1038/s41467-020-19961-w |
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author | Clements, Kristen E. Schleicher, Emily M. Thakar, Tanay Hale, Anastasia Dhoonmoon, Ashna Tolman, Nathanial J. Sharma, Anchal Liang, Xinwen Imamura Kawasawa, Yuka Nicolae, Claudia M. Wang, Hong-Gang De, Subhajyoti Moldovan, George-Lucian |
author_facet | Clements, Kristen E. Schleicher, Emily M. Thakar, Tanay Hale, Anastasia Dhoonmoon, Ashna Tolman, Nathanial J. Sharma, Anchal Liang, Xinwen Imamura Kawasawa, Yuka Nicolae, Claudia M. Wang, Hong-Gang De, Subhajyoti Moldovan, George-Lucian |
author_sort | Clements, Kristen E. |
collection | PubMed |
description | Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells. |
format | Online Article Text |
id | pubmed-7704667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77046672020-12-03 Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens Clements, Kristen E. Schleicher, Emily M. Thakar, Tanay Hale, Anastasia Dhoonmoon, Ashna Tolman, Nathanial J. Sharma, Anchal Liang, Xinwen Imamura Kawasawa, Yuka Nicolae, Claudia M. Wang, Hong-Gang De, Subhajyoti Moldovan, George-Lucian Nat Commun Article Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells. Nature Publishing Group UK 2020-11-30 /pmc/articles/PMC7704667/ /pubmed/33257658 http://dx.doi.org/10.1038/s41467-020-19961-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Clements, Kristen E. Schleicher, Emily M. Thakar, Tanay Hale, Anastasia Dhoonmoon, Ashna Tolman, Nathanial J. Sharma, Anchal Liang, Xinwen Imamura Kawasawa, Yuka Nicolae, Claudia M. Wang, Hong-Gang De, Subhajyoti Moldovan, George-Lucian Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens |
title | Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens |
title_full | Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens |
title_fullStr | Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens |
title_full_unstemmed | Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens |
title_short | Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens |
title_sort | identification of regulators of poly-adp-ribose polymerase inhibitor response through complementary crispr knockout and activation screens |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704667/ https://www.ncbi.nlm.nih.gov/pubmed/33257658 http://dx.doi.org/10.1038/s41467-020-19961-w |
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