Defects in CDK12 promote epigenetic plasticity through remodeling of the core transcription machinery (MeDIP-seq 2)

Here, we show that decrease in CDK12 activity depletes DNA methylation in vitro in prostate cancer cells and also in patient tumors of prostate, ovarian and breast cancer. DNA methylation is not lost from random loci but is particularly enriched for the MYC binding sites in prostate cancer.

CDK12 is the major transcription elongation kinase while MYC amplifies global transcription. We therefore reasoned that the core transcription machinery, in particular, the interactome of RNA polymerase II (RNA Pol II), must be adaptively remodeled for the cancer cells to tolerate decline in CDK12 activity. Indeed, unbiased mass spectrometry-profiling of RNA Pol II-interactome revealed that dual inhibition of CDK12, and its paralog CDK13, leads to a rapid recruitment of the DNA double strand (DS) break-sensing machinery to RNA Pol II.