ChIP-seq of cyclin-dependent kinases
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Richard Young
PROVIDER: E-GEOD-60027 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2013-12-23 | E-GEOD-50622 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-12-23 | E-GEOD-50625 | biostudies-arrayexpress
Project description:Several cyclin-dependent kinases (CDKs) are known to have roles in transcriptional regulation. The datasets presented here are ChIP-seq experiments for different CDKs and RNA polymerase II in murine embryonic stem cells and Jurkat cells.
2014-08-03 | GSE60027 | GEO
Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat, MM1S, Loucy, and HeLa (WT and Dox-inducible CDK7 mutant) cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2014-06-22 | E-GEOD-50624 | biostudies-arrayexpress
Project description:Herpesviruses encode conserved protein kinases to optimize virus infection by targeted phosphorylation. How these kinases bind to cellular factors and how this impacts their regulatory functions is poorly understood. Here, we use quantitative proteomics to determine the interactomes of eight herpesvirus kinases. We identify Cyclin A binding as a distinguishing feature of betaherpesvirus kinases that were previously described as viral mimics of cyclin-dependent kinases (v-CDKs), inert to cellular control. RXL motifs within the non-catalytic regions of roseolo- and muromegalovirus v-CDKs serve as Cyclin A docking sites and closely overlap with nuclear localization signals (NLS). By competing with NLS function, Cyclin A binding redirects NLS-RXL containing v-CDKs to cytoplasmic substrates at late times of infection. Concomitantly, Cyclin A is sequestered to the cytoplasm, which is essential for the viral inhibition of cellular DNA replication. Our data highlight a fine-tuned and physiologically important interplay between a cellular cyclin and viral CDK-like kinases.
2020-08-13 | PXD016334 | Pride
Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria-causing parasites have evolved unique cell-cycles with a repertoire of ancestral CDKs and cyclins whose functions and interdependency remain elusive. Here, we show that the divergent Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It phosphorylates canonical CDK motifs on components of the pre-replicative complex and is essential for DNA replication. We also provide evidence for indirect regulation of the concomitant progression through M-phase. Over a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2) with no evidence of SOC2 cycling through transcription, translation nor degradation. Our results present evidence that during Plasmodium gametogony, a unique and divergent cyclin/CDK pair evolved to fulfil the functional space of multiple eukaryotic cell-cycle kinases controlling S-phase entry and progression through M-phase.
2020-06-17 | GSE144743 | GEO
Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria parasites express ancestral CDKs and cyclins, whose functions and interdependency remain elusive. Here, we show that the unique Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It is essential for DNA replication and phosphorylates canonical S/TPxK CDK motifs on components of the pre-replicative complex otherwise regulated by distinct kinases in other eukaryotes. Over a replicative cycle, CRK5 stably interacts with a single Haemosporidia-specific cyclin (SOC2) with no evidence of SOC2 degradation. Regulation of CRK5 activity relies instead on dynamic phosphorylation of a C-terminus extension that mediates its interaction with SOC2. Our results present evidence that during the atypical cell cycles of Plasmodium gametogony, a unique and divergent cyclin/CDK pair fulfils the functional space of multiple eukaryotic cell-cycle kinases to initiate DNA replication.
2020-02-18 | PXD017283 | Pride
Project description:Cyclin dependent kinases (CDKs) lie at the heart of eukaryotic cell division, with different CDK complexes initiating DNA replication (S-CDKs) and mitosis (M-CDKs)1-3. However, the principles on which cyclin-CDKs organise the cell cycle are still contentious, with current theories suggesting that either M-CDKs and S-CDKs are redundant with each other, and simply serve as a source of CDK activity, or that they are functionally specialised and execute distinct tasks. Here we reconcile these two views, showing that although S-CDKs are unable to drive mitosis, global CDK phosphorylation in vivo between S-CDK and M-CDK is surprisingly similar. Remarkably, S-CDK has cryptic mitotic activity which can be exposed by the removal of Protein Phosphatase 1 (PP1). In particular, removal of centrosomal PP1 allows S-CDK to execute mitosis indistinguishably from M-CDK, demonstrating their functional redundancy. Thus, we reconcile the two opposing views of cell cycle control, showing that although there is a minor level of specialisation between S-CDKs and M-CDKs, that the core cell cycle engine is based upon modulation of CDK activity, with cyclins providing refinements to this core system.
2022-03-22 | PXD029073 | Pride
Project description:Cyclin-dependent kinases (Cdks) are the catalytic subunits of a family of mammalian heterodimeric serine/threonine kinases that play critical roles in control of cell-cycle progression, transcription and neuronal functions. To systematically investigate the regulations and functions of CDKs, we conducted a proteomic analysis of human CDK family and identified their associated protein complexes in two different cell lines using a modified SAINT (Significance Analysis of INTeractome) method. We discovered 753 HCIPs (high-confidence candidate interaction proteins) in HEK293T cells and 352 HCIPs in MCF10A cells.
2014-08-08 | PXD000593 | Pride
Project description:RNA Polymerase II transcribes protein-coding and many non-coding RNA genes in eukaryotes. The largest subunit of RNA Polymerase II, Rpb1, contains a hepta-peptide repeat on its C-terminal tail with three potential phosphorylation sites (Serine 2, Serine 5 and Serine 7). Mammalian Rpb1 contains 52 repeats. The phosphorylation events are catalyzed by specific protein kinases where the phosphorylation of specific residues is coupled to the transcription cycle. For example, the Cdk7 subunit of TFIIH phosphorylates both Serine 5 and Serine 7 during intiation and the Cdk9 subunit of P-TEFb phosphorylates Serine 2 during the transition into productive elongation. The dataset presented here is the genome-wide distribution of RNA Pol II with Serine 7 of the CTD phosphorylated in murine embryonic stem cells. This data, in addition to phospho-specific datasets generated in the same cell type in Rahl et al. Cell 2010 and Seila et al. Science 2008, represents the genome-wide distribution of multiple RNA Pol II isoforms in murine embryonic stem cells: total Pol II, hypophosphorylated CTD Pol II, Serine 2 phosphorylated CTD Pol II, Serine 5 phosphorylated CTD Pol II and Serine 7 phosphorylated CTD Pol II. An antibody specific to RNA Pol II Serine 7 phosphorylated CTD (gift of Dirk Eick; Chapman et al. Science 2008) was used to enrich for DNA fragments associated with this Pol II isoform in murine embryonic stem cells. DNA was purified and prepared for Illumina/Solexa sequencing following their standard protocol. This is a single dataset but together with datasets from Rahl et al. Cell 2010 and Seila et al. Science 2008, these datasets represent the genome-wide distribution of multiple RNA Pol II isoforms in murine embryonic stem cells: total Pol II, hypophosphorylated CTD Pol II, Serine 2 phosphorylated CTD Pol II, Serine 5 phosphorylated CTD Pol II and Serine 7 phosphorylated CTD Pol II.
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