Defects in CDK12 promote epigenetic plasticity through remodeling of the core transcription machinery (MeDIP-seq)

ABSTRACT: Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes a subset of cancers but it is not understood how cells adapt to decline in the activity of this major transcription elongation kinase. Here, we show that tolerance of the lowered CDK12 activity causes increased turnover of most of the transcriptome but leads to a selective stabilization of a subset of the mRNAs that augment mitochondrial efficiency. Transcriptional remodeling of the energy metabolism is also detected in CDK12 inactivated human tumors. Changes in transcription and mitochondrial activity predict decrease in DNA methylation, and we go on to show that either inhibition of CDK12 in vitro or inactivation of the CDK12 gene in prostate, ovarian and breast cancers deplete DNA methylation. We reasoned that the decrease in DNA methylation and the selective stabilization of the transcriptional program are explained through remodeling of the RNA polymerase II (RNA Pol II) interactome. Indeed, depletion of CDK12 activity leads to a rapid recruitment of DNA-dependent protein kinase (DNA-PK) to RNA Pol II. Combined inhibition of CDK12 and DNA-PK prevents activation of the CDK12 inhibitor-induced DNA damage response and initially augments the transcriptional defects followed by activation of cell death. Finally, we show that the loss of CDK12 activity sensitizes prostate, ovarian and breast cancer cells to DNA-PK inhibitors that are currently in clinical trials, and similar effects are also seen using genetic depletions. In brief, we show that the defects in transcription elongation lead to remodeling of the metabolism and the epigenome, which necessitate adaptive reconfiguration of the transcription machinery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262268 | GEO | 2026/05/15

REPOSITORIES: GEO