biostudies-literatureJi CHermann und Lilly Schilling-Stiftung für Medizinische ForschungDeutsche ForschungsgemeinschaftGraduate School of Life Sciences, Julius-Maximilians-Universität WürzburgInterdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburge55432https://www.ebi.ac.uk/biostudies/studies/S-EPMC9442301biostudies-literatureUnknown23(9)The P-TEFb complex promotes transcription elongation by releasing paused RNA polymerase II. P-TEFb itself is known to be inactivated through binding to the non-coding RNA 7SK but there is only limited information about mechanisms regulating their association. Here, we show that cells deficient in the RNA-binding protein hnRNP R, a known 7SK interactor, exhibit increased transcription due to phosphorylation of RNA polymerase II. Intriguingly, loss of hnRNP R promotes the release of P-TEFb from 7SK, accompanied by enhanced hnRNP A1 binding to 7SK. Additionally, we found that hnRNP R interacts with BRD4, and that hnRNP R depletion increases BRD4 binding to the P-TEFb component CDK9. Finally, CDK9 is stabilized upon loss of hnRNP R and its association with Cyclin K is enhanced. Together, our rEMBO reportshnRNP R negatively regulates transcription by modulating the association of P-TEFb with 7SK and BRD4.PMC9442301Fi573/20‐1Fi573/15‐2SE697/5‐2BR4910/1‐2SE697/4‐2BR4910/2‐2Fischer UJi CDeng CSendtner MSchneider CAntor KBischler TBriese MfalsehnRNP R negatively regulates transcription by modulating the association of P-TEFb with 7SK and BRD4.The P-TEFb complex promotes transcription elongation by releasing paused RNA polymerase II. P-TEFb itself is known to be inactivated through binding to the non-coding RNA 7SK but there is only limited information about mechanisms regulating their association. Here, we show that cells deficient in the RNA-binding protein hnRNP R, a known 7SK interactor, exhibit increased transcription due to phosphorylation of RNA polymerase II. Intriguingly, loss of hnRNP R promotes the release of P-TEFb from 7SK, accompanied by enhanced hnRNP A1 binding to 7SK. Additionally, we found that hnRNP R interacts with BRD4, and that hnRNP R depletion increases BRD4 binding to the P-TEFb component CDK9. Finally, CDK9 is stabilized upon loss of hnRNP R and its association with Cyclin K is enhanced. Together, our r2022-01-01T00:00:00Z2022 Sep2025-04-05T10:26:14.017Z2025-02-19T03:58:16.346ZS-EPMC94423013585639110.15252/embr.202255432