Fang Yin, Wang Yan, Spector Benjamin M, Xiao Xue, Yang Chao, Li Ping, Yuan Yuan, Ding Ping, Xiao Zhi-Xiong, Zhang Peixuan, Qiu Tong, Zhu Xiaofeng, Price David H, Li Qintong
Departments of Pediatrics and Obstetrics & Gynecology, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Center of Growth, Metabolism and Aging, College of Life Sciences, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
iScience. 2022 Aug 4;25(9):104844. doi: 10.1016/j.isci.2022.104844. eCollection 2022 Sep 16.
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.
睾丸生殖细胞肿瘤以及与之密切相关的胚胎干细胞对顺铂极为敏感，这一特性被认为与它们的多能状态和p53状态有关。细胞状态是否以及如何与p53协同作用以赋予顺铂敏感性仍不清楚。在此，我们报告正转录延伸因子b（P-TEFb）在DNA损伤时决定细胞命运。我们发现顺铂通过将P-TEFb从抑制性的7SK小核核糖核蛋白复合物中释放出来，从而迅速激活它。P-TEFb直接磷酸化多能因子雌激素相关受体β（ESRRB），并诱导其通过蛋白酶体降解，以增强促生存糖酵解。另一方面，P-TEFb是大部分p53靶基因转录所必需的，在长时间顺铂治疗期间触发细胞死亡。这些结果揭示了P-TEFb在协调DNA损伤反应方面以前未被充分认识的作用。我们讨论了使用P-TEFb抑制剂治疗癌症和改善顺铂诱导的耳毒性的意义。
