CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

Fan, Zheng; Devlin, Jennifer R.; Hogg, Simon J.; Doyle, Maria A.; Harrison, Paul F.; Todorovski, Izabela; Cluse, Leonie A.; Knight, Deborah; Sandow, Jarrod J.; Gregory, Gareth P.; Fox, Andrew; Beilharz, Traude H.; Kwiatkowski, Nicholas; Scott, Nichollas E.; Vidaković, Ana Tufegdžić; Kelly, Gavin; Svejstrup, Jesper Q.; Geyer, Matthias; Gray, Nathanael S.; Vervoort, Stephin J.; Johnstone, Ricky W.

doi:10.1126/sciadv.aaz5041

Cited by 113 publications

(108 citation statements)

References 45 publications

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“…1C,D), we nevertheless probed the RNA-seq data for evidence that CDK12 inhibition was occurring. Others have shown that CDK12 inhibition results in premature, intronic polyadenylation (iPA) (Dubbury et al 2018;Krajewska et al 2019;Fan et al 2020), which causes reduced exon read counts toward gene 3 ′ ends. A DEXSeq analysis (Anders et al 2012) showed no evidence for iPA genome-wide in cells treated with SY-351 (Supplemental Fig.…”

Section: Inhibition Of Cdk7 Causes Diverse and Widespread Splicing Changesmentioning

confidence: 99%

Selective inhibition of CDK7 reveals high-confidence targets and new models for TFIIH function in transcription

et al. 2020

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CDK7 associates with the 10-subunit TFIIH complex and regulates transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Few additional CDK7 substrates are known. Here, using the covalent inhibitor SY-351 and quantitative phosphoproteomics, we identified CDK7 kinase substrates in human cells. Among hundreds of high-confidence targets, the vast majority are unique to CDK7 (i.e., distinct from other transcription-associated kinases), with a subset that suggest novel cellular functions. Transcription-associated factors were predominant CDK7 substrates, including SF3B1, U2AF2, and other splicing components. Accordingly, widespread and diverse splicing defects, such as alternative exon inclusion and intron retention, were characterized in CDK7-inhibited cells. Combined with biochemical assays, we establish that CDK7 directly activates other transcription-associated kinases CDK9, CDK12, and CDK13, invoking a "master regulator" role in transcription. We further demonstrate that TFIIH restricts CDK7 kinase function to the RNAPII CTD, whereas other substrates (e.g., SPT5 and SF3B1) are phosphorylated by the three-subunit CDK-activating kinase (CAK; CCNH, MAT1, and CDK7). These results suggest new models for CDK7 function in transcription and implicate CAK dissociation from TFIIH as essential for kinase activation. This straightforward regulatory strategy ensures CDK7 activation is spatially and temporally linked to transcription, and may apply toward other transcription-associated kinases.

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Section: Inhibition Of Cdk7 Causes Diverse and Widespread Splicing Changesmentioning

confidence: 99%

Selective inhibition of CDK7 reveals high-confidence targets and new models for TFIIH function in transcription

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…CDKs regulating gene expression apart from cell cycle control constitute additional therapeutic targets. Specifically, the CDKs 7/8/9/12/13 are involved in RNA polymerase II transcription regulation [50][51][52]. Though the complexity exceeds the scope of this review, we included some information gathered from HNSCC and GBM studies inhibiting these CDK's.…”

Section: Cdk7/8/9/12/13 Inhibitorsmentioning

confidence: 99%

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Riess

Irmscher

Salewski

et al. 2020

Cancer Metastasis Rev

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Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

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“…The studies suggested that the identified substrates of CDKL5 kinase might be important biomarkers in the diagnosis and treatment of CDKL5 disorders. Additionally, the CDK12 and CDK13 have been identified as fundamental regulators of the global PolII processivity and transcription elongation [ 96 , 97 , 98 , 99 , 100 ].…”

Section: Analog-sensitive Kinase Technologymentioning

confidence: 99%

Phosphoproteomics Meets Chemical Genetics: Approaches for Global Mapping and Deciphering the Phosphoproteome

Jurcik

Siváková

Cipakova

et al. 2020

IJMS

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Protein kinases are important enzymes involved in the regulation of various cellular processes. To function properly, each protein kinase phosphorylates only a limited number of proteins among the thousands present in the cell. This provides a rapid and dynamic regulatory mechanism that controls biological functions of the proteins. Despite the importance of protein kinases, most of their substrates remain unknown. Recently, the advances in the fields of protein engineering, chemical genetics, and mass spectrometry have boosted studies on identification of bona fide substrates of protein kinases. Among the various methods in protein kinase specific substrate identification, genetically engineered protein kinases and quantitative phosphoproteomics have become promising tools. Herein, we review the current advances in the field of chemical genetics in analog-sensitive protein kinase mutants and highlight selected strategies for identifying protein kinase substrates and studying the dynamic nature of protein phosphorylation.

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CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

Cited by 113 publications

References 45 publications

Selective inhibition of CDK7 reveals high-confidence targets and new models for TFIIH function in transcription

Selective inhibition of CDK7 reveals high-confidence targets and new models for TFIIH function in transcription

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Phosphoproteomics Meets Chemical Genetics: Approaches for Global Mapping and Deciphering the Phosphoproteome

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