Biomaterial Database

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes. 2019

Anil Paul Chirackal Manavalan, and Kveta Pilarova, and Michael Kluge, and Koen Bartholomeeusen, and Michal Rajecky, and Jan Oppelt, and Prashant Khirsariya, and Kamil Paruch, and Lumir Krejci, and Caroline C Friedel, and Dalibor Blazek

Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic.

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.

UI	MeSH Term	Description	Entries
D010766	Phosphorylation	The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.	Phosphorylations
D004260	DNA Repair	The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones.	DNA Damage Response
D004261	DNA Replication	The process by which a DNA molecule is duplicated.	Autonomous Replication,Replication, Autonomous,Autonomous Replications,DNA Replications,Replication, DNA,Replications, Autonomous,Replications, DNA
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012319	RNA Polymerase II	A DNA-dependent RNA polymerase present in bacterial, plant, and animal cells. It functions in the nucleoplasmic structure and transcribes DNA into RNA. It has different requirements for cations and salt than RNA polymerase I and is strongly inhibited by alpha-amanitin. EC 2.7.7.6.	DNA-Dependent RNA Polymerase II,RNA Pol II,RNA Polymerase B,DNA Dependent RNA Polymerase II
D045325	HCT116 Cells	Human COLORECTAL CARCINOMA cell line.	HCT 116 Cells,HCT-116 Cells,Cell, HCT 116,Cell, HCT-116,Cell, HCT116,Cells, HCT 116,Cells, HCT-116,Cells, HCT116,HCT 116 Cell,HCT-116 Cell,HCT116 Cell
D059585	G1 Phase Cell Cycle Checkpoints	Regulatory signaling systems that control the progression of the CELL CYCLE through the G1 PHASE and allow transition to S PHASE when the cells are ready to undergo DNA REPLICATION. DNA DAMAGE, or the deficiencies in specific cellular components or nutrients may cause the cells to halt before progressing through G1 phase.	G1 Cell Cycle Arrest,G1 Cell Cycle Checkpoints,G1 Phase Checkpoints,G1 Phase Restriction Point,G1 Restriction Point,G1-S Phase Cell Cycle Checkpoint,START Cell Cycle Checkpoint,Checkpoint, G1 Phase,Checkpoints, G1 Phase,G1 Phase Checkpoint,G1 Restriction Points,G1 S Phase Cell Cycle Checkpoint,Restriction Point, G1,Restriction Points, G1
D018844	Cyclin-Dependent Kinases	Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events.	Cyclin-Dependent Kinase,Cyclin-Dependent Protein Kinase,cdk Proteins,Cyclin-Dependent Protein Kinases,Cyclin Dependent Kinase,Cyclin Dependent Kinases,Cyclin Dependent Protein Kinase,Cyclin Dependent Protein Kinases,Kinase, Cyclin-Dependent,Kinase, Cyclin-Dependent Protein,Protein Kinase, Cyclin-Dependent