Lecture will be held in English

Hosted by

Dalibor Blažek

About the lecture

Transcriptional CDKs and phosphatases: keeping RNA polymerase II on track and on time

 Cyclin-dependent kinases (CDKs) and phosphoprotein phosphatases cooperate to control transitions in the RNA polymerase II (RNAPII) transcription cycle. To dissect the CDK network, we helped develop a new chemical-genetic tool: a bump-hole PROTAC (BH-PROTAC) that targets kinases with enlarged ATP-binding sites. In engineered cells harboring an analog-sensitive (AS) CDK7—a kinase with roles in both the cell cycle and transcription initiation—a BH-PROTAC induces selective degradation of CDK7 and its regulatory subunits. This provides a chemical-genetic complementation system, in which we replace CDK7^as with BH-PROTAC-resistant mutant variants to elucidate upstream signaling pathways. By another chemical-genetic approach, we revealed that CDK9 phosphorylates the elongation factor SPT5 in three different regions to trigger promoter-proximal pause release and tune the elongation rate of RNAPII. Finally, we showed that protein phosphatase 4 (PP4), a candidate tumor suppressor in prostate cancer (PCa), opposes CDK9 to stabilize the promoter-proximal pause. Disrupting CDK9 control over RNAPII elongation—by mutating phosphorylation sites in SPT5 or removing PP4—leads to RNA-processing defects, non-productive transcription and deranged gene expression. Moreover, PCa cells lacking PP4 activity have elevated levels of nascent transcription and are resistant to growth inhibition by a CDK9 degrader, suggesting that PP4 helps set the threshold of kinase activity needed for RNAPII elongation, and that a relaxed requirement for CDK9 in PP4-deficient cells might contribute to tumor promotion.

Registration for lunch with the speaker /for Ph.D. students/

The sponsored lunch usually takes place in the Campus River restaurant. Please meet the speaker and other students at 12:45 at the reception desk at the main entrance (building B22, see the map below).