Testicular germ cell tumors and closely related embryonal stem cells are exquisitely
sensitive to cisplatin, a feature thought to be linked to their pluripotent state and p53
status. More...
Testicular germ cell tumors and closely related embryonal stem cells are exquisitely
sensitive to cisplatin, a feature thought to be linked to their pluripotent state and p53
status. It remains unclear whether and how cellular state is coordinated with p53 to
confer cisplatin sensitivity. Here, we report that positive transcription elongation factor b
(P-TEFb) determines cell fate upon DNA damage. We find that cisplatin rapidly
activates P-TEFb by releasing it from inhibitory 7SK small nuclear ribonucleoprotein
complex. P-TEFb directly phosphorylates pluripotency factor estrogen related receptor
beta (ESRRB), and induces its proteasomal degradation to enhance pro-survival
glycolysis. On the other hand, P-TEFb is required for the transcription of a substantial
portion of p53 target genes, triggering cell death during prolonged cisplatin treatment.
These results reveal previously underappreciated roles of P-TEFb to coordinate the
DNA damage response. We discuss the implications for using P-TEFb inhibitors to
treat cancer and ameliorate cisplatin-induced ototoxicity. Less...