Revisiting the Function of CDK7 in Transcription by Virtue of a Recently Described TFIIH Kinase Inhibitor

Coin, Frédéric; Egly, Jean‐Marc

doi:10.1016/j.molcel.2015.08.006

Cited by 18 publications

(17 citation statements)

References 12 publications

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“…10). Currently, several laboratories are developing inhibitors of cyclin-dependent kinases (CDK) that have a critical role in regulating transcription initiation, pause release, and elongation (e.g., CDK7, CDK8, or CDK9), the three main steps involved in RNA synthesis (11,12). Other approaches are inhibition of DNA repair mechanisms (e.g., irinotecan, topotecan, olaparib; ref.…”

Section: Introductionmentioning

confidence: 99%

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Núñez

Robles

Giraudon

et al. 2016

Molecular Cancer Therapeutics

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128

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We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Núñez

Robles

Giraudon

et al. 2016

Molecular Cancer Therapeutics

Self Cite

128

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“…However, THZ1-induced inhibition of IEG transcription in this study may not be solely attributable to defects in RNAPII stalling. Using an in vitro transcription system with Hela nuclear extract (Nilson et al, 2015 ) demonstrated that THZ1 not only causes defects in RNAPII CTD phosphorylation and promoter proximal stalling, but also in co-transcriptional capping and productive elongation, meanwhile with minimal effects on transcription initiation, thus revealed unexpected function of Cdk7 in RNAPII stalling and mRNA capping (Coin and Egly, 2015 ). It is interesting to examine whether the above regulatory machinery is conserved in post-mitotic neurons.…”

Section: Discussionmentioning

confidence: 99%

Cdk7 Is Required for Activity-Dependent Neuronal Gene Expression, Long-Lasting Synaptic Plasticity and Long-Term Memory

Yang

Guo

et al. 2017

Front. Mol. Neurosci.

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In the brain, de novo gene expression driven by learning-associated neuronal activities is critical for the formation of long-term memories. However, the signaling machinery mediating neuronal activity-induced gene expression, especially the rapid transcription of immediate-early genes (IEGs) remains unclear. Cyclin-dependent kinases (Cdks) are a family of serine/threonine kinases that have been firmly established as key regulators of transcription processes underling coordinated cell cycle entry and sequential progression in nearly all types of proliferative cells. Cdk7 is a subunit of transcriptional initiation factor II-H (TFIIH) and the only known Cdk-activating kinase (CAK) in metazoans. Recent studies using a novel Cdk7 specific covalent inhibitor, THZ1, revealed important roles of Cdk7 in transcription regulation in cancer cells. However, whether Cdk7 plays a role in the regulation of transcription in neurons remains unknown. In this study, we present evidence demonstrating that, in post-mitotic neurons, Cdk7 activity is positively correlated with neuronal activities in cultured primary neurons, acute hippocampal slices and in the brain. Cdk7 inhibition by THZ1 significantly suppressed mRNA levels of IEGs, selectively impaired long-lasting synaptic plasticity induced by 4 trains of high frequency stimulation (HFS) and prevented the formation of long-term memories.

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“…These events facilitate the release of the RNA Pol II and activate the productive elongation phase of transcription ( Figure 1C) (Adelman and Lis, 2012;Jonkers and Lis, 2015). Furthermore, CDK9-dependent phosphorylations play a key role in the recruitment of the 3'end processing and splicing factors, responsible for messenger RNA (mRNA) maturation (Yang et al, 2005;Coin and Egly, 2015).…”

Section: How Cdk9 Workmentioning

confidence: 99%

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

et al. 2020

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Cyclin-Dependent Kinases (CDKs) are well-known reliable targets for cancer treatment being often deregulated. Among them, since the transcription-associated CDK9 represents the sentry of cell transcriptional homeostasis, it can be a valuable target for managing cancers in which the transcriptional machinery is dysregulated by tumor-driver oncogenes. Here we give an overview of some natural compounds identified as CDK inhibitors with reported activity also against CDK9, that were taken as a model for the development of highly active synthetic anti-CDK9 agents. After, we summarize the data on CDK9 inhibition in a group of rare pediatric solid tumors such as rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma and malignant rhabdoid tumors (soft tissue sarcomas), highlighting the more recent results in this field. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.

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Revisiting the Function of CDK7 in Transcription by Virtue of a Recently Described TFIIH Kinase Inhibitor

Cited by 18 publications

References 12 publications

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Cdk7 Is Required for Activity-Dependent Neuronal Gene Expression, Long-Lasting Synaptic Plasticity and Long-Term Memory

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

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