Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity

Testicular germ cell tumors and closely related embryonal stem cells are exquisitelysensitive to cisplatin, a feature thought to be linked to their pluripotent state and p53status. It remains unclear whether and how cellular state is coordinated with p53 toconfer cisplatin sensitivity. Here, we report that positive transcription elongation factor b(P-TEFb) determines cell fate upon DNA damage. We find that cisplatin rapidlyactivates P-TEFb by releasing it from inhibitory 7SK small nuclear ribonucleoproteincomplex. P-TEFb directly phosphorylates pluripotency factor estrogen related receptorbeta (ESRRB), and induces its proteasomal degradation to enhance pro-survivalglycolysis. On the other hand, P-TEFb is required for the transcription of a substantialportion of p53 target genes, triggering cell death during prolonged cisplatin treatment.These results reveal previously underappreciated roles of P-TEFb to coordinate theDNA damage response. We discuss the implications for using P-TEFb inhibitors totreat cancer and ameliorate cisplatin-induced ototoxicity.