Structural and Functional Analysis of the Cdk13/Cyclin K Complex

Greifenberg, Ann Katrin; Hönig, Dana; Pilařová, Květa; Düster, Robert; Bartholomeeusen, Koen; Bösken, Christian A.; Anand, K.; Blažek, Dalibor; Geyer, Matthias

doi:10.1016/j.celrep.2015.12.025

Cited by 123 publications

(150 citation statements)

References 40 publications

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“…CDK12 and its homolog CDK13 (containing a virtually identical kinase domain) associate with CCNK to form two functionally distinct complexes CCNK/CDK12 and CCNK/CDK13 . Transcription of several core homologous recombination (HR) DNA repair genes, including BRCA1, FANCD2, FANCI, and ATR, is CDK12‐dependent . In agreement, treatment with low concentrations of THZ531 resulted in down‐regulation of a subset of DNA repair pathway genes.…”

Section: Introductionmentioning

confidence: 79%

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

et al. 2019

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CDK12 is a kinase associated with elongating RNA polymerase II (RNAPII) and is frequently mutated in cancer. CDK12 depletion reduces the expression of homologous recombination (HR) DNA repair genes, but comprehensive insight into its target genes and cellular processes is lacking. We use a chemical genetic approach to inhibit analog‐sensitive CDK12, and find that CDK12 kinase activity is required for transcription of core DNA replication genes and thus for G1/S progression. RNA‐seq and ChIP‐seq reveal that CDK12 inhibition triggers an RNAPII processivity defect characterized by a loss of mapped reads from 3′ends of predominantly long, poly(A)‐signal‐rich genes. CDK12 inhibition does not globally reduce levels of RNAPII‐Ser2 phosphorylation. However, individual CDK12‐dependent genes show a shift of P‐Ser2 peaks into the gene body approximately to the positions where RNAPII occupancy and transcription were lost. Thus, CDK12 catalytic activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects as a consequence of CDK12 inactivation underlie the genome instability phenotype observed in many cancers.

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Section: Introductionmentioning

confidence: 79%

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

et al. 2019

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“…They are involved in gene transcription and Pre-mRNA Splicing [22][23][24]. Recent studies have shown that aberrant levels of CDK13 were associated with several cancers.…”

Section: Discussionmentioning

confidence: 99%

CDK13 RNA Over-Editing Mediated by ADAR1 Associates with Poor Prognosis of Hepatocellular Carcinoma Patients

Dong

Chen

Cai

et al. 2018

Cell Physiol Biochem

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Background/Aims: Aberrant RNA editing, mediated by adenosine deaminases acting on RNA (ADAR), serves as a post-transcriptional event participating in tumorigenesis and prognosis. However, the RNA editing profiles during HCC progression and their clinical correlations remain unclear. Methods: Multiple tissue samples were collected from an advanced HCC patient. RNA-seq was performed to obtain the RNA editing profiles for each sample. Two RNA editing sites from CDK13 were further validated in 60 HCC patients; and their potential regulatory mechanisms were investigated. Results: In-depth analysis of the RNA-seq data revealed a significant number of editing sites (632-816) in coding regions for each tissue sample, showing branched evolution during tumorigenesis and metastasis. Two editing sites (Q103R and K96R) in CDK13 showed significant over-editing in tumor, and these phenomenon were validated in 60 HCC patients. Furthermore, the clinicopathological analysis revealed that these CDK13 over-editing sites were positively associated with TNM, PVTT and poor prognosis. In addition, the editing level of these sites were significantly correlated with the expression of ADAR1. Loss of function assays further proved that these CDK13 over-editing sites were mediated by ADAR1 in HCC cells. Conclusions: CDK13 RNA over-editing sites mediated by ADAR1 may serve as novel cancer driver events in HCC progression.

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“…The family contains 20 members which can be divided into the cell‐cycle kinases (including CDK1,2,3,4, and 6) and the transcriptional CDKs (including CDK12, 13, 9, 8, and 7) . CDK12 is very closely related and highly homologous to CDK13, and the ATP binding sites of these proteins are essentially identical; however, knockdown of CDK13 affects different genes compared to CDK12, having effects on growth signaling pathways . From the outset, we concluded that selectivity between CDK12 and CDK13 would be extremely difficult to obtain, so we initially focused on obtaining selectivity over CDK9 and CDK7 as transcriptional CDKs, and CDK2 and 1 as representative and well‐known examples of the cell‐cycle CDKs.…”

Section: Published Pan‐cdk Inhibitor Dinaciclib and Dual Ck1δ/ck1ϵ Inmentioning

confidence: 99%

Structure‐Based Design of Selective Noncovalent CDK12 Inhibitors

Johannes

Denz

et al. 2018

ChemMedChem

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Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP-ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Further structure-guided optimization delivered a series of selective CDK12 inhibitors, including compound 7 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Profiling of this compound across CDK9, 7, 2, and 1 at high ATP concentration, single-point kinase panel screening against 352 targets at 0.1 μm, and proteomics via kinase affinity matrix technology demonstrated the selectivity. This series of compounds inhibits phosphorylation of Ser2 on the C-terminal repeat domain of RNA polymerase II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells.

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Structural and Functional Analysis of the Cdk13/Cyclin K Complex

Cited by 123 publications

References 40 publications

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

CDK13 RNA Over-Editing Mediated by ADAR1 Associates with Poor Prognosis of Hepatocellular Carcinoma Patients

Structure‐Based Design of Selective Noncovalent CDK12 Inhibitors

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