Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity.
Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity.
复制标题
DOI：
10.1016/j.isci.2022.104844
复制
发表时间：
2022-09-16
期刊：
影响因子：
5.8
通讯作者：
Li, Qintong
中科院分区：
文献类型：
--
作者：
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
睾丸生殖细胞肿瘤和密切相关的胚胎干细胞对顺铂非常敏感，这一特征被认为与其多能状态和p53状态有关。目前尚不清楚细胞状态是否以及如何与p53协调以赋予顺铂敏感性。在这里，我们报告，正转录延伸因子B（P-TEF B）决定细胞的命运后，DNA损伤。我们发现，顺铂通过将P-TEFb从抑制性7SK小核核糖核蛋白复合物中释放而快速激活P-TEFb。P-TEFb直接磷酸化多能性因子雌激素相关受体β（ESRRB），并诱导其蛋白酶体降解以增强促存活糖酵解。另一方面，P-TEFb是大部分p53靶基因转录所必需的，在长期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损伤反应中的作用。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影响。P-TEFb在DNA损伤反应期间调节促存活和促死亡途径P-TEFb促进ESRRB蛋白酶体降解以增强促存活糖酵解P-TEFb诱导相当大一部分p53靶基因触发细胞死亡P-TEFb的化学抑制剂阻断顺铂或UV诱导的细胞死亡分子生物学;基因调节的分子机制;癌症
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. P-TEFb regulates pro-survival and pro-death pathways during DNA damage response P-TEFb promotes ESRRB proteasomal degradation to enhance pro-survival glycolysis P-TEFb induces a substantial portion of p53 target genes to trigger cell death Chemical inhibitors of P-TEFb blocks cisplatin- or UV-induced cell death Molecular biology; Molecular mechanism of gene regulation; Cancer
登录
查看更多内容
影响因子：
45.3
作者：
Einhorn, Lawrence H.;Brames, Mary J.;Williams, Stephen D.
通讯作者：
Williams, Stephen D.
DOI：
10.1007/978-1-4939-8861-7_4
发表时间：
2019-01-01
期刊：
BCL-2 FAMILY PROTEINS
影响因子：
--
作者：
Fraser, Cameron;Ryan, Jeremy;Sarosiek, Kristopher
通讯作者：
Sarosiek, Kristopher
影响因子：
0.7
作者：
Cavallo, Francesca;Feldman, Darren R.;Barchi, Marco
通讯作者：
Barchi, Marco
影响因子：
9
作者：
通讯作者：
--
影响因子：
8
作者：
Fischer M
通讯作者：
Fischer M