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To probe this response, we developed a cell line resistant to an inhibitor targeting CDK12 and its paralog, CDK13. CDK13 can compensate for the loss of CDK12, which is why we used the dual inhibitor THZ531. Targeted drug screening of the parental and resistant cell lines revealed cross\u2010resistance to other transcriptional kinases but no clear acquired point of vulnerability. Using genome\u2010wide mapping of mRNA\u2010stabilization based on metabolic labelling of RNA, we report selective mRNA stabilization of factors promoting oxidative phosphorylation in the resistant cells. We go on to show that loss of CDK12 activity enhances ATP production both in cell line models and in patient tumours. Finally, we show that dual inhibition of CDK12\/13 results in excessive phosphorylation of the DNA damage H2AX in prostate cancer cells but not in our CDK12\/13 inhibitor\u2010resistant model system. In brief, we propose that inactivation of\n                    <jats:italic>CDK12<\/jats:italic>\n                    rewires cellular energy metabolism to suppress DNA damage.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71101","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T03:54:38Z","timestamp":1774670078000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inactivation of\n                    <scp>\n                      <i>CDK12<\/i>\n                    <\/scp>\n                    Enhances Mitochondrial Efficiency to Suppress\n                    <scp>DNA<\/scp>\n                    Damage"],"prefix":"10.1111","volume":"30","author":[{"given":"Aishwarya","family":"Gondane","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Developmental Biology, Faculty of Medicine University of Helsinki  Helsinki 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