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Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1
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Inactivation of CDK12 Enhances Mitochondrial Efficiency to Suppress DNA Damage

Aishwarya Gondane1, Shivani Yalala1, Jing Liang1

  • 1Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Journal of Cellular and Molecular Medicine
|March 28, 2026
PubMed

Insights

Prostate cancer cells lacking cyclin-dependent kinase 12 (CDK12) adapt by boosting energy production. This metabolic rewiring helps suppress DNA damage, offering new therapeutic insights.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Metabolic Engineering

Background:

  • Cyclin-dependent kinase 12 (CDK12) inactivation is observed in some prostate cancers.
  • The cellular adaptation mechanisms to CDK12 loss remain unclear.
  • CDK13 can functionally compensate for CDK12, necessitating dual inhibition studies.

Purpose of the Study:

  • To investigate cellular adaptation to CDK12 inhibition.
  • To identify vulnerabilities and compensatory mechanisms in prostate cancer cells with reduced CDK12 activity.
  • To explore the impact of CDK12/13 inhibition on cellular metabolism and DNA damage response.

Main Methods:

  • Development of a drug-resistant cell line using a dual CDK12/13 inhibitor (THZ531).
  • Targeted drug screening of parental and resistant cell lines.
  • Genome-wide mRNA stabilization mapping via RNA metabolic labeling.
  • Assessment of ATP production and H2AX phosphorylation in cell models and patient tumors.

Main Results:

  • Resistant cells showed cross-resistance to other transcriptional kinase inhibitors.
  • Selective mRNA stabilization of oxidative phosphorylation factors was observed in resistant cells.
  • Loss of CDK12 activity enhanced ATP production in cell lines and patient tumors.
  • Dual CDK12/13 inhibition induced DNA damage (H2AX phosphorylation) in sensitive cells but not resistant ones.

Conclusions:

  • CDK12 inactivation triggers a metabolic rewiring towards enhanced oxidative phosphorylation.
  • This metabolic adaptation in prostate cancer cells may serve to suppress DNA damage.
  • Understanding this adaptive response is crucial for developing targeted therapies against CDK12-deficient prostate cancers.
Keywords:
SLAM‐seqacquired resistancecyclin‐dependent kinase 12genomic instabilitymetabolismprostate cancertranscription elongation

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