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

Autor: Ford K; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Munson BP; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA.; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Fong SH; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA.; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Panwala R; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Chu WK; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Rainaldi J; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA.; Biomedical Sciences Program, University of California San Diego, La Jolla, CA, 92093, USA., Plongthongkum N; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Arunachalam V; Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA., Kostrowicki J; Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA., Meluzzi D; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Kreisberg JF; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Jensen-Pergakes K; Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA., VanArsdale T; Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA., Paul T; Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA., Tamayo P; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Zhang K; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA., Bienkowska J; Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA. Jadwiga.R.Bienkowska@pfizer.com., Mali P; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA. pmali@ucsd.edu., Ideker T; Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA. tideker@health.ucsd.edu.; Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA. tideker@health.ucsd.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 May 11; Vol. 13 (1), pp. 7678. Date of Electronic Publication: 2023 May 11.
DOI: 10.1038/s41598-023-33329-2
Abstrakt: 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.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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