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Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation

Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and rela...

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Autores principales: Ford, Kyle, Munson, Brenton P., Fong, Samson H., Panwala, Rebecca, Chu, Wai Keung, Rainaldi, Joseph, Plongthongkum, Nongluk, Arunachalam, Vinayagam, Kostrowicki, Jarek, Meluzzi, Dario, Kreisberg, Jason F., Jensen-Pergakes, Kristen, VanArsdale, Todd, Paul, Thomas, Tamayo, Pablo, Zhang, Kun, Bienkowska, Jadwiga, Mali, Prashant, Ideker, Trey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175263/
https://www.ncbi.nlm.nih.gov/pubmed/37169829
http://dx.doi.org/10.1038/s41598-023-33329-2
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author Ford, Kyle
Munson, Brenton P.
Fong, Samson H.
Panwala, Rebecca
Chu, Wai Keung
Rainaldi, Joseph
Plongthongkum, Nongluk
Arunachalam, Vinayagam
Kostrowicki, Jarek
Meluzzi, Dario
Kreisberg, Jason F.
Jensen-Pergakes, Kristen
VanArsdale, Todd
Paul, Thomas
Tamayo, Pablo
Zhang, Kun
Bienkowska, Jadwiga
Mali, Prashant
Ideker, Trey
author_facet Ford, Kyle
Munson, Brenton P.
Fong, Samson H.
Panwala, Rebecca
Chu, Wai Keung
Rainaldi, Joseph
Plongthongkum, Nongluk
Arunachalam, Vinayagam
Kostrowicki, Jarek
Meluzzi, Dario
Kreisberg, Jason F.
Jensen-Pergakes, Kristen
VanArsdale, Todd
Paul, Thomas
Tamayo, Pablo
Zhang, Kun
Bienkowska, Jadwiga
Mali, Prashant
Ideker, Trey
author_sort Ford, Kyle
collection PubMed
description Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and related factors, identifying 43 synthetic-lethal and 12 synergistic interactions. We dissect CDK perturbations using single-cell RNAseq, for which we develop a novel computational framework to precisely quantify cell-cycle effects and diverse cell states orchestrated by specific CDKs. While pairwise disruption of CDK4/6 is synthetic-lethal, only CDK6 is required for normal cell-cycle progression and transcriptional activation. Multiple CDKs (CDK1/7/9/12) are synthetic-lethal in combination with PRMT5, independent of cell-cycle control. In-depth analysis of mRNA expression and splicing patterns provides multiple lines of evidence that the CDK-PRMT5 dependency is due to aberrant transcriptional regulation resulting in premature termination. These inter-dependencies translate to drug–drug synergies, with therapeutic implications in cancer and other diseases.
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spelling pubmed-101752632023-05-13 Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation Ford, Kyle Munson, Brenton P. Fong, Samson H. Panwala, Rebecca Chu, Wai Keung Rainaldi, Joseph Plongthongkum, Nongluk Arunachalam, Vinayagam Kostrowicki, Jarek Meluzzi, Dario Kreisberg, Jason F. Jensen-Pergakes, Kristen VanArsdale, Todd Paul, Thomas Tamayo, Pablo Zhang, Kun Bienkowska, Jadwiga Mali, Prashant Ideker, Trey Sci Rep Article Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and related factors, identifying 43 synthetic-lethal and 12 synergistic interactions. We dissect CDK perturbations using single-cell RNAseq, for which we develop a novel computational framework to precisely quantify cell-cycle effects and diverse cell states orchestrated by specific CDKs. While pairwise disruption of CDK4/6 is synthetic-lethal, only CDK6 is required for normal cell-cycle progression and transcriptional activation. Multiple CDKs (CDK1/7/9/12) are synthetic-lethal in combination with PRMT5, independent of cell-cycle control. In-depth analysis of mRNA expression and splicing patterns provides multiple lines of evidence that the CDK-PRMT5 dependency is due to aberrant transcriptional regulation resulting in premature termination. These inter-dependencies translate to drug–drug synergies, with therapeutic implications in cancer and other diseases. Nature Publishing Group UK 2023-05-11 /pmc/articles/PMC10175263/ /pubmed/37169829 http://dx.doi.org/10.1038/s41598-023-33329-2 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ford, Kyle
Munson, Brenton P.
Fong, Samson H.
Panwala, Rebecca
Chu, Wai Keung
Rainaldi, Joseph
Plongthongkum, Nongluk
Arunachalam, Vinayagam
Kostrowicki, Jarek
Meluzzi, Dario
Kreisberg, Jason F.
Jensen-Pergakes, Kristen
VanArsdale, Todd
Paul, Thomas
Tamayo, Pablo
Zhang, Kun
Bienkowska, Jadwiga
Mali, Prashant
Ideker, Trey
Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation
title Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation
title_full Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation
title_fullStr Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation
title_full_unstemmed Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation
title_short Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation
title_sort multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175263/
https://www.ncbi.nlm.nih.gov/pubmed/37169829
http://dx.doi.org/10.1038/s41598-023-33329-2
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