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We show that mutations in the\n                    <jats:italic>CDK12<\/jats:italic>\n                    gene are associated with decreased DNA methylation in patient tumours and dual inhibition of the major transcription elongation kinases, CDK12 and CDK13 decreases DNA methylation in\u00a0vitro. This decrease in DNA methylation occurs particularly in the target genes of MYC (MYC Proto\u2010Oncogene). Previously, it was established that CDK12 inhibition impairs homologous recombination, while increase in MYC activity causes DNA replication stress. We therefore hypothesized that CDK12\/13 inhibition renders cells dependent on high DNA\u2010PK activity, which is required for non\u2010homologous end joining. Indeed, we show that genetic and pharmacological targeting of DNA\u2010PK is toxic to cancer cells in combination with CDK12\/13 inhibition. In brief, here we show that decrease in CDK12\/13 activity depletes DNA methylation from MYC target genes and propose that\n                    <jats:italic>CDK12<\/jats:italic>\n                    inactivation may serve as a biomarker of sensitivity to DNA\u2010PK inhibitors.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71323","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:57:06Z","timestamp":1787288226000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>CDK12<\/scp>\n                    \/13 Inhibition Induces\n                    <scp>DNA<\/scp>\n                    Hypomethylation and Sensitizes Cancer Cells to Compounds Targeting\n                    <scp>DNA<\/scp>\n                    \u2010\n                    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