CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

Sci Adv. 2020 Apr 29;6(18):eaaz5041. doi: 10.1126/sciadv.aaz5041.

Zheng Fan ¹ ², Jennifer R Devlin ¹ ², Simon J Hogg ¹, Maria A Doyle ¹ ², Paul F Harrison ³ ⁴, Izabela Todorovski ¹ ², Leonie A Cluse ¹, Deborah A Knight ¹, Jarrod J Sandow ⁵ ⁶, Gareth Gregory ¹, Andrew Fox ¹, Traude H Beilharz ³, Nicholas Kwiatkowski ⁷ ⁸, Nichollas E Scott ⁹, Ana Tufegdzic Vidakovic ¹⁰, Gavin P Kelly ¹¹, Jesper Q Svejstrup ¹⁰, Matthias Geyer ¹², Nathanael S Gray ⁷ ⁸, Stephin J Vervoort ¹³ ², Ricky W Johnstone ¹³ ²

Affiliations

1 The Peter MacCallum Cancer Centre, Melbourne, 3000 VIC, Australia.
2 The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3052 VIC, Australia.
3 Monash Biomedicine Discovery Institute, Monash University, Clayton, 3800 VIC, Australia.
4 Monash Bioinformatics Platform, Monash University, Clayton, 3800 VIC, Australia.
5 Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia.
6 Department of Medical Biology, University of Melbourne, Melbourne, 3052 VIC, Australia.
7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
8 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
9 Department of Microbiology and Immunology, Peter Doherty Institute, University of Melbourne, Parkville, 3052 VIC, Australia.
10 Mechanisms of Transcription Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
11 Bioinformatics and Biostatistics, The Francis Crick Institute, London NW1 1AT, UK.
12 Institute of Structural Biology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
13 The Peter MacCallum Cancer Centre, Melbourne, 3000 VIC, Australia. [email protected] [email protected].

PMID: 32917631 DOI: 10.1126/sciadv.aaz5041

Abstract

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.

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