期刊
SCIENCE ADVANCES
卷 6, 期 18, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aaz5041
关键词
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资金
- Cancer Council Victoria
- NHMRC [454569]
- Victorian Cancer Agency Early Career Seed Grant
- Melbourne Research Scholarship
- The Kids' Cancer Project
- Rubicon Fellowship from the Netherlands Organization for Scientific Research (NWO) [019.161LW.017]
- Peter MacCallum Cancer Centre Foundation
- Australian Cancer Research Foundation
- Victorian Government's Operational Infrastructure Support Program
- Francis Crick Institute from Cancer Research UK [FC001166]
- UK Medical Research Council [FC001166]
- Wellcome Trust [FC001166]
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 CDK1 2 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 CDK1 2 and CDK13 and identify both as fundamental regulators of global POLII processivity and transcription elongation.
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