GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE287nnn/GSE287819/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE287819GEOGSEfalseDefective CDK12 remodels the transcription machinery to promote epigenetic plasticity (SLAM-seq)Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes a subset of cancers but it is not known how cells benefit from this, which is necessary to selectively eliminate these mutant cells. 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. Combined targeting of CDK12 and the catalytic subunit of the DS break-sensing complex, DNA-PK, significantly suppresses MYC-dependent transcription and RNA Pol II phosphorylation, and these events are followed by activation of the cell death response. Finally, we show that decrease in CDK12 activity sensitizes also ovarian and breast cancer cells to DNA-PK inhibition. In brief, we show that defects in transcription elongation promote epigenetic plasticity to sustain oncogenic transcriptional program, which opens an actionable therapeutic vulnerability.2026/08/26GSE287819GSM8751938GSM8751939GSM8751941GSM8751942GSM8751940GSM8751945GSM8751943GSM875194430173287819Homo sapiens[42625328]