CDK13 cooperates with CDK12 to control global RNA polymerase II processivity
Zheng Fan1,2, Jennifer R Devlin1,2, Simon J Hogg1
1The Peter MacCallum Cancer Centre, Melbourne, 3000 VIC, Australia.
Science Advances
|September 12, 2020
Summary
Cyclin-dependent kinases CDK12 and CDK13 regulate RNA polymerase II (POLII) transcription. Dual inhibition of these kinases causes cell death by impairing POLII elongation and processivity.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- The RNA polymerase II (POLII) transcription cycle is regulated by cyclin-dependent kinases (CDKs) and cyclins.
- The specific roles of CDK12 and CDK13 in transcriptional elongation and processivity are not well understood.
Purpose of the Study:
- To investigate the individual and shared roles of CDK12 and CDK13 in regulating POLII transcription.
- To elucidate the molecular mechanisms by which CDK12 and CDK13 control transcription elongation and processivity.
Main Methods:
- Generated analog-sensitive kinase variants of CDK12 and CDK13 using CRISPR-Cas9 homology-directed repair.
- Assessed the effects of single and dual inhibition of CDK12 and CDK13 on cellular transcription and viability.
- Analyzed genome-wide transcriptional changes and POLII CTD phosphorylation status.
Main Results:
- Single inhibition of CDK12 or CDK13 triggered transcriptional responses linked to growth signaling or DNA damage, with minimal impact on cell viability.
- Dual inhibition of CDK12 and CDK13 led to potent cell death, extensive genome-wide transcriptional alterations, and widespread alternative 3' polyadenylation.
- Molecularly, dual inhibition resulted in loss of POLII CTD phosphorylation and significantly reduced POLII elongation rates and processivity.
Conclusions:
- CDK12 and CDK13 exhibit substantial functional redundancy in regulating transcription.
- Both CDK12 and CDK13 are fundamental regulators of global POLII processivity and transcription elongation.
- Targeting both CDK12 and CDK13 simultaneously offers a potent strategy for inducing cell death through transcription disruption.
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