2. Academic Validation
  3. Dual Modes of Gene Regulation by CDK12

Dual Modes of Gene Regulation by CDK12

  • bioRxiv. 2025 Sep 23:2025.09.22.677923. doi: 10.1101/2025.09.22.677923.
Yubao Wang 1 2,  Apoorva Baluapuri 2 3 4,  Cherubin Manokaran 1 2,  Jing Ni 1 2,  Tao Jiang 1 2,  Roel C Janssens 5,  Jurgen A Marteijn 5,  Karen Adelman 2 3 4,  Jean Zhao 1 2,  Thomas M Roberts 1 2 6
Affiliations

Affiliations

  • 1 Departments of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 The Eli and Edythe L. Broad Institute, Cambridge MA 02142, USA.
  • 4 Ludwig Center at Harvard, Boston, MA 02115, USA.
  • 5 Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Centre, Rotterdam, the Netherlands.
  • 6 Lead contact.
PMID: 41040222 DOI: 10.1101/2025.09.22.677923
Abstract

The process of transcription is driven forward by the activity of kinases including CDK7, CDK9 and CDK12. Accordingly, acute inhibition of any of these kinases results in profound downregulation of gene expression. Here, we discover that loss or inhibition of CDK12 also significantly upregulates a set of coding and non-coding loci, whose activation could contribute to the anti-proliferative effects of CDK12 inhibitors. Mechanistically, CDK12 inhibition impairs transcription elongation, leading to increased RNA polymerase II termination or arrest in long genes. However, short genes such as MYC and enhancer RNAs are highly transcribed in the absence of CDK12 activity. Indeed, in HER2+ breast Cancer, a malignancy where CDK12 is co-amplified with HER2 and its expression correlates with disease status, CDK12 inhibition markedly elevates MYC expression to induce lethality. The dual effects of CDK12 inhibition elucidated herein clarify its role in transcriptional control and have significant translational implications.

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