학술논문
Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation.
Document Type
Article
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
Source
Subject
*CYCLIN-dependent kinases
*GENETIC transcription regulation
*RNA splicing
*GENE expression
*RNA sequencing
*CRISPRS
*SMALL nuclear RNA
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Language
ISSN
2045-2322
Abstract
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. [ABSTRACT FROM AUTHOR]