CDK13 cooperates with CDK12 to control global RNA polymerase II processivity.
Zheng FanJennifer R DevlinSimon J HoggMaria A DoylePaul F HarrisonIzabela TodorovskiLeonie A CluseDeborah A KnightJarrod J SandowGareth Peter GregoryAndrew FoxTraude H BeilharzNicholas KwiatkowskiNichollas E ScottAna Tufegdzic VidakovicGavin P KellyJesper Q SvejstrupMatthias GeyerNathanael S GrayStephin J VervoortRicky W JohnstonePublished in: Science advances (2020)
The RNA polymerase II (POLII)-driven transcription cycle is tightly regulated at distinct checkpoints by cyclin-dependent kinases (CDKs) and their cognate cyclins. The molecular events underpinning transcriptional elongation, processivity, and the CDK-cyclin pair(s) involved remain poorly understood. Using CRISPR-Cas9 homology-directed repair, we generated analog-sensitive kinase variants of CDK12 and CDK13 to probe their individual and shared biological and molecular roles. Single inhibition of CDK12 or CDK13 induced transcriptional responses associated with cellular growth signaling pathways and/or DNA damage, with minimal effects on cell viability. In contrast, dual kinase inhibition potently induced cell death, which was associated with extensive genome-wide transcriptional changes including widespread use of alternative 3' polyadenylation sites. At the molecular level, dual kinase inhibition resulted in the loss of POLII CTD phosphorylation and greatly reduced POLII elongation rates and processivity. These data define substantial redundancy between CDK12 and CDK13 and identify both as fundamental regulators of global POLII processivity and transcription elongation.
Keyphrases
- cell cycle
- transcription factor
- dna damage
- cell proliferation
- cell death
- crispr cas
- gene expression
- genome wide
- signaling pathway
- high glucose
- protein kinase
- computed tomography
- magnetic resonance
- dna methylation
- diabetic rats
- tyrosine kinase
- magnetic resonance imaging
- quantum dots
- copy number
- machine learning
- heat shock
- drug induced
- big data
- electronic health record
- living cells
- cell cycle arrest
- induced apoptosis
- contrast enhanced